Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].[CH3:13][O:14][CH2:15]Cl.CO>O1CCCC1.O>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH3:15])([CH3:5])[CH3:4]
Reactant: COCCl
Reactant: CC(C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Firstly, sodium hydride (275 mmol) was suspended in tetrahydrofuran (THF) (120 ml) and to this, 2-isopropylphenol (111 mmol, reference symbol A1 in FIG. 1) dissolved in THF (30 ml) was added dropwise at 0° C. After 30 minutes, chloromethyl methyl ether (221 mmol) was added to this solution and after heating to room temperature, the reaction was stopped by adding methanol and then water. The aqueous phase was extracted with ether. The organic phases were combined and washed with water and a saturated sodium chloride solution in that order and then dried using anhydrous sodium sulfate. After removing the drying agent by filtering, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 1-isopropyl-2-methoxy methoxybenzene (17.5 g, 87% yield, reference symbol A2 in FIG. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]=[C:13]=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CCN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCN=C=O)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
4.53 g (30 mol) of 4-methoxy-β-phenylethylamine are added dropwise to a solution of 2.96 g (10.0 mol) of triphosgene in 30 ml of dry tetrahydrofuran and the mixture is heated at the boiling point for 2 hours. The solution is cooled to room temperature and filtered and the filtrate is concentrated in vacuo. The colorless oil which remains is purified by bulb tube distillation under a pressure of 2 mmHg at a bath temperature of 220° C. to give 1.1 g of 4-methoxy-β-phenylethyl isocyanate. 0.7 g (4.0 mmol) of 4-methoxy-β-phenylethyl isocyanate and 0.4 g (3.5 mmol) of 3-ethyl-4-methyl-2-oxo-3-pyrroline are stirred with one another and the mixture is heated at 150° C. for one hour. The cooled reaction mixture is dissolved in a minimum of ethyl acetate and purified by column chromatography over silica gel 60 with the aid of the mobile phase ethyl acetate (Rf =0.5). After the eluent has been evaporated off under reduced pressure, 0.25 g of methoxy-4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido)-ethyl]-benzene is obtained, and is introduced in portions into chlorosulfonic acid cooled to 0° C. After being stirred at 0° C. for one hour, this reaction mixture is poured onto ice. The sulfonic acid chloride which has precipitated is taken up in ethyl acetate. The organic phase is dried with sodium sulfate and concentrated in vacuo to give the sulfonic acid chloride as a crude product, which is dissolved in acetone and converted into 2-methoxy-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-1-carboxamido)-ethyl]-benzenesulfonamide with aqueous ammonia solution. The sulfonamide has a melting point of 204°-205° C.
Reaction SMILES: CN(C=O)C.CS([O:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[CH3:38][O:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47].C([O-])([O-])=O.[K+].[K+]>O>[F:35][C:23]([F:36])([C:24]1([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][O:10][C:42]2[CH:43]=[C:44]([O:48][CH3:49])[C:45]([O:46][CH3:47])=[C:40]([O:39][CH3:38])[CH:41]=2)[O:16][N:15]=1)=[O:37]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCc2cc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)no2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a DMF (1.0 mL) solution of the compound (20.8 mg) obtained in Example 3-(5) and 3,4,5-trimethoxyphenol (16.0 mg), K2CO3 (24.0 mg) was added and the mixture was stirred at room temperature for 30 minutes, then at 50° C. for 2 hours. The reaction mixture was added to water (20 mL) and the organic layer extracted with AcOEt (20 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by PTLC(NH-form) to give the titled compound (20.5 mg, colorless amorphous.)
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:15](CC#N)=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12](=[O:25])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.Cl.[C:27]([OH:30])(=[O:29])[CH3:28]>>[Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:28][C:27]([OH:30])=[O:29])=[N:14][N:13]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:12](=[O:25])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c2cccc(Br)c2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Reactant: CC(=O)O
Agent: Cl
Product: Cn1c2cccc(Br)c2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 4.8 g (12.2 mmol) of 9-bromo-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in a mixture of 190 ml of acetic acid and of 50 ml of concentrated hydrochloric acid is heated at reflux for 6 h. The solution is concentrated under reduced pressure and the residue is taken up in a mixture of dichloromethane and of water. Basification is carried out with 30% sodium hydroxide solution, separation is carried out by settling and extraction is carried out with dichloromethane. The aqueous phase is acidified with concentrated hydrochloric acid while cooling with an ice bath. The precipitate is collected by filtration, washed with water and dried under reduced pressure. 3.1 g (7.5 mmol) of solid are obtained.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:12]([OH:14])=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C([N+]#[C-])(C)(C)C>O1CCOCC1>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:12](=[O:14])[C@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:3][CH:1]=[O:2])[CH3:16]
Reactant: O=CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: [C-]#[N+]C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC=O
Yield: 55.2 %

Procedure:
A solution of 3.9 g (20 mM) N-formyl-L-phenylalanine, 2.5 g (24 mM) glycine ethyl ester, and 1.7 g (20 mM) tert-butyl isonitrile in 30 ml dioxane was heated at 40°-50°C for 28 hours. It was then evaporated to dryness, and the residue was dissolved in 300 ml methylene chloride. The solution was washed as in the preceding examples, dried, and evaporated. The residue was crystallized from carbon tetrachloride and petroleum ether to produce 3.1 g N-formyl-L-phenylalanyl-glycine ethyl ester (48 percent yield based on the glycine ethyl ester).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>ClCCl.O>[CH3:19][O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccc(Br)c(C)c1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
To a solution of 10.00 g 4-bromo-3-methylaniline in 50 ml dichloromethane was added 80 ml of a 10% solution of sodium bicarbonate in water. The mixture was cooled to 0° C. and 6.2 ml (7.62 g) methyl chloroformate was added during 10 min. with stirring. The reaction mixture was stirred at room temperature for 1 h. The phases were separated. The organic phase was washed with a 10% solution of citric acid in water, 10% solution of sodium bicarbonate in water and brine, dried with magnesium sulfate and evaporated to yield 12.94 g of (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester as light brown solid melting at 71-72° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH3:1][CH:2]([CH3:5])[CH2:3][S:4][CH2:8][CH2:7][C:6]#[N:9]
Reactant: CC(C)CS
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: CC(C)CSCCC#N

Procedure:
β-(2-Methyl-1-propylmercapto)propionitrile was prepared according to the procedure of Example 1 using 2-methyl-1-propanethiol (25.0 g; 0.28 moles), acrylonitrile (14.9 g; 0.28 moles) and sodium methoxide (0.5 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:7]([O:27][CH3:28])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([C:4](=[O:29])[C:3]([OH:30])=[O:2])[CH:6]=[C:7]([O:27][CH3:28])[C:8]=1[O:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1
Reactant: COC(=O)C(=O)c1cc(OC)c(OCCOc2ccc3ccccc3c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)C(=O)O)cc(OC)c1OCCOc1ccc2ccccc2c1
Yield: 93.2 %

Procedure:
A solution of 3,5-dimethoxy-4- [2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.45 g of purified 3,5-dimethoxy-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 114°-116° C.
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:58][CH2:59][NH:60][C:61](=[O:62])[C:39]=12)C1C=CC=CC=1>>[Cl:57][C:54]1[CH:55]=[CH:56][C:51]([C:46]2([CH2:45][C:41]3[N:40]4[CH2:58][CH2:59][NH:60][C:61](=[O:62])[C:39]4=[C:38]([OH:37])[C:43](=[O:44])[N:42]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:52][CH:53]=1
Reactant: O=C1NCCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c21
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: O=C1NCCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(O)c21

Procedure:
This compound was prepared following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (517).
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([O-:9])=[O:8].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:28]([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)(=[O:32])[CH:29]([CH3:31])[CH3:30].[N+](C1C=CC=CC=1N)([O-])=O.N1C=CC=CC=1>C(OCC)(=O)C>[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])=[CH:42][CH:41]=1)([O-:9])=[O:8]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(C)C(=O)Nc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(2'-Nitrophenyl)-4-isobutyrylaminobenzamide is prepared under the reaction conditions given in Example 5: after the addition of pyridine/o-nitroaniline, the reaction solution is stirred for 15 hours at ambient temperature and for 5 hours at boiling temperature, the following components being used: 54.6 g (74.68 mMole) dimethylformamide, 1.5 L dry ethyl acetate, 37.3 g (29.42 mMole) oxalyl chloride, 47 g (22.63 mMole) 4-isobutyrylaminobenzoic acid, 34.4 g (24.89 mMole) o-nitroaniline, and 25.6 g (32.36 mMole) pyridine. The product is recrystallized from ethyl acetate. Yield 13.3 g (18% of theory); m.p. 237.6° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].N1CCOCC1.Cl[C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([C:38]4[C:29](=[CH:30][C:31]5[O:36][CH2:35][CH2:34][O:33][C:32]=5[CH:37]=4)[O:28][CH2:27]3)[C:19]2=[O:39])[CH:14]=[CH:13][CH:12]=1.ClC1N=CC(CN2C3C(=CC=CC=3)C3(C4C(=CC5OCCOC=5C=4)OC3)C2=O)=CC=1>>[CH3:1][N:2]([CH3:3])[C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([C:38]4[C:29](=[CH:30][C:31]5[O:36][CH2:35][CH2:34][O:33][C:32]=5[CH:37]=4)[O:28][CH2:27]3)[C:19]2=[O:39])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1N(Cc2cccc(Cl)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CNC
Agent: O=C1N(Cc2ccc(Cl)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Solvent: C1COCCN1
Product: CN(C)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 32 and making non-critical variations using dimethylamine (40% w/w in water) to replace morpholine and 1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-[(6-chloropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 196-197° C.; 1H NMR (300 MHz, CDCl3) δ7.45-7.34 (m, 1H), 7.24-7.11 (m, 2H), 7.06-6.94 (m, 2H), 6.52-6.46 (m, 2H), 6.42-6.35 (m, 1H), 6.28 (s, 1H), 4.91 (ABq, J=53.2, 15.3 Hz, 2H), 4.80 (ABq, J=84.8, 9.1 Hz, 2H), 4.23-4.07 (m, 4H), 3.04 (s, 6H); 13C NMR (300 MHz, CDCl3) δ 177.4, 159.0, 155.3, 153.3, 144.5, 142.7, 138.2, 137.9, 132.2, 128.6, 123.5, 123.1, 121.2, 111.7, 109.9, 108.8, 104.5, 99.3, 80.3, 64.5, 63.9, 58.1, 46.0, 37.8; MS (ES+) m/z 430.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21]4[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[N:22]=4)=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH:38]1([NH:43][C:26]([C:23]2[N:22]=[C:21]([C:19]3[CH:18]=[N:17][C:13]4[O:14][CH2:15][CH2:16][N:11]([S:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)(=[O:10])=[O:9])[C:12]=4[CH:20]=3)[O:25][N:24]=2)=[O:27])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCC1
Reactant: O=C(Cl)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCC1)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Reaction time: 72 h
Yield: 32.7 %

Procedure:
To a suspension of 5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carbonyl chloride (21 mg, 0.049 mmol) in DCE (5 mL) was added DIPEA (21 μL, 120 μmol) to form a clear solution. To that solution was added cyclopentyl amine (40 μL, 0.099 mmol) and saturated aqueous NaHCO3 (1 mL). The reaction was stirred for 72 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography to provide N-cyclopentyl-5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carboxamide (7.7 mg, 0.016 mmol, 32.2%) as a white solid. LCMS (+ESI) m/z=474.1 [M+H]+; 1H-NMR (CDCl3) δ 8.90 (d, 1H), 8.87 (d, 1H), 7.75 (m, 2H), 7.21 (m, 2H), 6.97 (m, 1H), 4.47 (m, 1H), 4.09 (dd, 2H), 3.92 (dd, 2H), 2.13 (m, 2H), 1.82-1.52 (m, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: OB(O)c1cccc(F)c1
Product: CNCC1Cc2cccc(-c3cccc(F)c3)c2O1

Procedure:
The title compound was prepared (0.38 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-fluorophenylboronic acid (0.173 g, 1.24 mmol). mp 160-163° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:14].CI>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1([CH3:1])[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCCCN1C(=O)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of diisopropyl amine (2.11 g, 25.86 mmol) in THF (50 mL) at 0° C. was added nBuLi (9.4 mL, 23.51 mmol, 2.5M in hexanes). This solution was stirred for 15 min at 0° C. and then cooled to -78° C. Ethyl-1-benzoyl-piperidine-2-carboxylate (6.16 g, 23.5 mmol) was added and the reaction was allowed to stir for 45 min at which time methyl iodide (3.34 g, 23.51 mmol) was added. The reaction was warmed to room temperature and gently warmed (~40° C.) for 2 h. The reaction was quenched with NaHCO3, extracted with ether, dried over Na2SO4 and concentrated to give ethyl-1-benzoyl-2-methyl-piperidine-2-carboxylate (6.49 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ1.10 (m, 3H), 1.45 (s, 3H), 1.4-1.7 (comp m, 4H), 2.90 (m, 2H), 3.5 (m, 2H), 4.14 (m, 2H), 7.24 (m, 5H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10]N1CCN=C1.[OH:16][S:17]([OH:20])(=O)=[O:18].O=S(=O)=O.C(=O)([O-])[O-].[Ca+2]>>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[NH:10][C:2]1[NH:1][C:5]2[CH:6]=[C:7]([S:17]([OH:20])(=[O:18])=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: C1=NCCN1Nc1nc2ccccc2[nH]1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)=O
Agent: [Ca+2]
Product: O=S(=O)(O)c1ccc2nc(NC3=NCCN3)[nH]c2c1
Temperature: 100 °C

Procedure:
2-(Benzimidazolylamino-2-imidazoline (5.00g) was treated cautiously with oleum (20 ml). The resulting solution was stirred and heated at 100°C for 11/2 hours. After cooling the solution was poured into ice/water (500 ml). Solid calcium carbonate was then added until the pH was 6.5. The white suspension was brought to the boil and the calcium sulphate filtered from the hot solution. The filtrate was concentrated under reduced pressure, brought to the boil again and filtered to remove a trace of insoluble material. The filtrate was acidified with glacial acetic acid and allowed to stand. A crystalline solid (3.98 g) separated on cooling. Recrystallisation from boiling water gave 2-(2-Imidazoline-2-ylamino)benzimidazole-5-sulphonic acid (1.16g) as colourless microcrystals. m.p. >360°C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl.[CH3:11]O>>[CH3:11][O:8][C:7](=[O:9])[C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Reaction time: 16 h

Procedure:
A suspension of 4(R)-hydroxyproline (35.12 g, 267.8 mmol) in methanol (500 ml) was saturated with gaseous hydrochloric acid. The resulting solution was allowed to stand for 16 hrs and the solvent evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.CO.[Fe]>[O:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:11][N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(-c2cnco2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of 5-(4-nitro-phenyl)-oxazole (2.0 g, 10.5 mmol), iron powder (2.4 g, 42.8 mmol) in acetic acid (5 ml) and methanol (30 ml) was stirred at 60° C. for 1 hour. After filtration through a pad of celite under suction, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (3:4 followed by 3:2) to give 4-oxazol-5-yl-phenyl-amine (1.4 g, 83% yield). 1H NMR (acetone-d6) δ 5.0 (br s, 2H, NH), 6.76 (d, 2H, J=8.7 Hz, Ar), 7.12 (s, 1H, Ar), 7.45 (d, 2H, J=8.6 Hz, Ar), 8.04 (s, 1H, Ar).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH:27]=[CH2:28])[C:5]1=[O:6])[CH:2]=[CH2:3].[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:20][N:19]1[NH:18][C:17]([O:21][CH2:22][C:23]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[O:25])=[CH:16]/[C:15]/1=[C:10]1\[N:11]=[C:12]2[C:13](=[O:14])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:6])[N:7]([CH2:26][CH:27]=[CH2:28])[C:8]2=[N:9]\1
Reactant: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2c(n(CC=C)c1=O)=N/C(=C1/C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2
Yield: 27 %

Procedure:
Condensation of 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and N-phenyl-piperazine (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 105.2 %

Procedure:
To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at −40° C. under N2. After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-ethoxy-3-{4-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as yellow solid.