Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:19]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)c1cccc(Cl)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (0.17 g, 0.6 mmol) (from Example 5b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 5 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.17 g, 76.9%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:12]1[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][N:13]=1
Reactant: NCCCCCO
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Product: Cc1ccc(Cc2cnc(NCCCCCO)[nH]c2=O)cn1

Procedure:
Reaction of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone with 5-aminopentanol at 170°-180° gave 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which was isolated as the dihydrochloride salt m.p. 215°-217°.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:15]([NH:18][CH:19]=O)([CH3:17])[CH3:16].P(Cl)(Cl)(Cl)=O>>[CH:15]([N:18]=[CH:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)([CH3:17])[CH3:16]
Reactant: CC(C)NC=O
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N=CN1c2ccccc2Cc2ccccc21

Procedure:
Reaction of acridan, isopropylformamide and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-[(ISOPROPYLIMINO)METHYL]ACRIDAN, m.p. 149.5°-150.5° C. (corr.), from n-hexane.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][N:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:8]=2[N:9]=[C:10](Cl)[CH:11]=1)=[O:5])C.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([C:10]2[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7]3[C:15](/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][N:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:8]=3[N:9]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1
Reactant: OB(O)c1ccc(O)cc1
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: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1
Yield: 78.9 %

Procedure:
To a solution of 6-chloro-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (2.8 g, 6.80 mmol) in dioxane (60 ml) were added 4-hydroxyphenylboronic acid (1.03 g, 7.48 mmol) and an aqueous solution of cesium carbonate (0.4M, 30 mL). The resulting solution was degassed using argon, tetrakis(triphenylphosphine)palladium (0.71 g, 0.61 mmol) was then added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, methylene chloride and water were added, and the mixture was acidified until pH=2. The organic layer was washed with water and the aqueous phase was extracted using methylene chloride. The resulting organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.37 g, 79%) as a yellow solid which was used without any further purification.
Reaction SMILES: [Mg].[CH3:2]I.[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO.CCOCC>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([NH2:16])[CH3:2])=[CH:7][CH:6]=1
Reactant: N#CCCCCCOc1ccc(Cl)cc1
Reactant: CI
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(N)CCCCCOc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
Magnesium (120 mg, 5 mmol) was added to Et2O (15 mL), followed by Methyl iodide (310 μl, 5 mmol). After reflux has ceased, the mixture was heated to reflux for 20 min. The solution was than cooled to 0° C. and 6-(4-chloro-phenoxy)-hexanenitrile (1119 mg, 5 mmol) was added. The ice bath was removed and the mixture was stirred at ambient temperature for 20 h. The mixture was then diluted with dry THF (5 mL) ad cooled to −78° C. NaBH4 (190 mg, 5 mmol) was added followed by MeOH (3.5 ml) and stirring was continued at −78° C. for 4.5 h. The reaction was quenched by careful addition of 1M aqueous HCl (20 mL). The layers were separated, the aqueous layer was washed with Et2O (1×25 mL), the organic layer was extracted with 1M aqueous HCl (3×30 mL). The aqueous layers were adjusted to pH 12 by addition of 10M aqueous NaOH (8 mL) and extracted with EtOAc (3×50 mL). The combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound (ca 30% of total by integration of HPLC trace at 218 nm) together with two more hydrophobic byproducts (total: 766 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[N:12][CH2:13][C:14]#[CH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].O>C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[CH3:1][CH:2]1[CH2:11][CH:10]([NH:12][CH2:13][C:14]#[CH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: C#CCN=C1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CCNC1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 11.9 %

Procedure:
To a solution of (2-methyl-4-prop-2-ynylimino-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (0.5 g) in acetic acid (20 ml), sodium triacetoxyborohydride was added in small amounts (1.75 g) under stirring at room temperature. The reaction mixture was then stirred at room temperature for one hour and poured on 100 ml of cold water under stirring. The desired compound was filtered after precipitation. The compound was dissolved in ethyl acetate and washed with water. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduce pressure to give a brown oil which was purified by flash chromatography with cyclohexane/ethyl acetate (95/5) as eluent and then cyclohexane/ethyl acetate (90/10) to give a mixture of diastereoisomere cis-trans (50–50) of (2-methyl-4-prop-2-ynylamino-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (0.06 g, 17.6% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15](O)=[O:16])[C:6]=2[CH:18]=1.C1C=CC2N(O)N=[N:31][C:29]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN>CN(C=O)C>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15]([NH:31][CH3:29])=[O:16])[C:6]=2[CH:18]=1
Reactant: CN(c1cc2oc(C3=CCCC3)c(C(=O)O)c2cc1Br)S(C)(=O)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of 5-bromo-2-(cyclopent-1-en-1-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (3.5 g, 7.70 mmol), HOBT (1.6 g, 11.55 mmol) and EDCI (2.2 g, 11.55 mmol) in dry DMF (40 mL) was stirred at 25° C. After 2 hours, Et3N (2.4 g, 23.11 mmol) and MeNH2 (1.6 g, 23.11 mmol) were added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H2O (50 mL) and extracted with EtOAc (50 mL*3), and dried over Na2SO4. After concentration, the residue was purified by column chromatography (DCM) to give the product of 5-bromo-2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (2 g, yield: 56%). 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.59 (s, 1H), 6.70 (t, J=3.2 Hz, 1H), 5.95 (s, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 3.06 (s, 3H), 2.76˜2.81 (m, 2H), 2.58˜2.62 (m, 2H), 2.07 (t, J=7.6 Hz, 2H). MS (M+H)+: 427/429.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[K+].O.Cl>CO>[CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C#CC2CC2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C#CC2CC2)cn1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a small flask were added methyl 5-(cyclopropylethynyl)picolinate (240 mg, 1.193 mmol) and potassium hydroxide (147 mg, 2.62 mmol) in MeOH (4 ml). The mixture was stirred at 50° C. for 20 min. It was cooled to RT and the solvent was reduced. The white solid was treated with small amount of water (˜1.5 mL), and acidified by 6N HCl to pH 2. The light brown precipitate was formed and the resulting mixture was cooled to 0° C. by ice bath. The brown precipitate was collected by filtration to yield 5-(cyclopropylethynyl)picolinic acid (163 mg, 0.871 mmol, 73.0% yield) as light yellow solid. It was dried in high vacuum for overnight and was used directly for next step. MS m/z=188.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][OH:16])[CH3:11])=[CH:6][CH:5]=1)[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]2[CH:50]=[CH:49][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]3=[O:48])=[CH:20][CH:19]=2)[CH3:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)=NOCCO)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Yield: 99.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 447 mg of 2-[1-(4-ethoxyphenyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 29), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.34 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: CC(C)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (2-methylpropanoyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (29a) (11 g, 22 mmol) dissolved in 120 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 3.9 g (60 mmol) of sodium azide (NaN3). After work-up, the crude material (29b) was used in the next step without further purification. MS (ESI) m/z 522.08 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:28][N:29]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:28][NH2:29])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 77.8 %

Procedure:
[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-ethyl]-carbamic acid tert-butyl ester (1.1 g, 1.92 mmol) was treated with hydrazine hydrate (0.5 ml, 9 mmol) in EtOH (5 ml) at rt over night to give [(S)-1-aminomethyl-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-carbamic acid tert-butyl ester (640 mg, 75%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]([C:35]([OH:37])=[O:36])[CH2:26][CH2:25][O:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CO.C1(C)C=CC=CC=1>[F:39][C:9]([F:38])([F:8])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]([C:35]([O:37][CH3:1])=[O:36])[CH2:26][CH2:25][O:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C(=O)O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Yield: 73 %

Procedure:
Trimethylsilyldiazomethane (2.0M in hexanes, 3.5 mL, 7 mmol) was added in portions over 1 hour to a solution of (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxylic acid (WO 00/56727A1; 3.2 g, 6.9 mmol) in a mixture of methanol (10 mL) and toluene (7 mL). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (80:20), to give the title compound as a colorless solid (2.4 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([F:10])=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:6]([F:10])=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1cc(Cl)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
3,4-Dichloro-6-fluoroaniline (1 equivalent, prepared as described in U.S. Pat. No. 6,126,917) was reacted with 4-chloro-6-nitroquinazoline (3.5 equivalents, prepared by reacting 6-nitroquinazoline with thionyl chloride, according to known procedures), in iso-propylalcohol. After filtration, 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline (compound 1) was obtained in 60% yield. m.p.=270–271° C.; MS (m/z): 353.2, 355.2 (M+); 1H-NMR: δ=6.97 (d, 1H), 7.345 (d, 1H), 7.885 (d, 1H), 8.405 (d, 1H), 8.554 (dd, 1H), 8.8 (d, 1H) ppm. HPLC conditions: C-18 column, 55% acetate buffer, PH=3.8/45% acetonitrile, flow=1 ml/min; r.t.=7.15 minutes.
Reaction SMILES: ClCl.[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1.C1C(=O)N([Cl:18])C(=O)C1>>[Cl:18][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:3])[N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(Cl)n1
Agent: ClCl
Product: ClCc1cccc(Cl)n1

Procedure:
MS (ESI) 162, 164, 166 (M+H)+, Cl2 pattern. Prepared from 6-chloro-2-picoline and NCS in place of NBS.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:26])=[O:27])=[O:19]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A mixture of tert-butyl ({2-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate 79 (0.35 g, 0.67 mmol) and Pd/C (10%, 0.12 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 80 (0.25 g, 88.96) as a white foam.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br.O>C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC(C2=C(Cl)C(=O)CCC2)C1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
Using acetic acid as solvent. A solution of 3-(2-chloro-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one (5.12 g) in glacial acetic acid (50 ml) was treated with 48% HBr in acetic acid (2 ml). After 12 hours the reaction mixture was poured on to water and the resulting precipitate removed by filtration to yield the title compound m.p. 192°-3° C. (EtOAc).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1.[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:33](Cl)=[O:34])[C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1>O>[CH2:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:33]([C:27]1[C:28]2[C:29](=[O:32])[C:30]3[C:21](=[CH:20][CH:19]=[C:18]([CH3:17])[CH:31]=3)[S:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)=[O:34])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Reactant: CC(C)CNCC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2sc3cccc(C(=O)N(CC(C)C)CC(C)C)c3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
1.0 g (7.75 mmoles) of diisobutyl amine is dropped into a toluene solution of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride (0.22 g, 0.78 mmoles). After 2 hours at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed with water. A crude oil is obtained after evaporation of the solvent. 11.5 mg of a yellow solid are isolated by flash chromatography of the crude oil (SiO2— eluent: CH2Cl2:MeOH 96:4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[N:29]([C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37])=[C:30]=[O:31]>ClCCCl>[CH3:38][C:33]1[C:32]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([CH:14]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])[CH2:10][CH2:9]3)=[C:4]([F:28])[CH:3]=2)=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
A mixture of 2-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (1.0 mmol) in DCE (10 mL) was stirred at rt for 16 h. The precipitate that had formed was collected by filtration and dried under vacuum to give the title compound (78 mg, 50%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28; m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 7.95-7.75 (br s, 1H), 7.40-7.20 (m, 5H), 7.30-6.90 (br s, 1H), 6.80-6.70 (m, 2H), 3.60-3.10 (m, 7H), 2.45-2.35 (m, 2H), 2.28 (s, 3H), 2.20-2.10 (m, 4H), 2.00-1.90 (m, 1H), 1.52-1.40 (m, 1H), 1.35-1.20 (m, 2H), 1.18-1.03 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:18])[CH:12]=1)(=O)C>O.CO>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:18]
Reactant: CC(=O)Oc1cccc(C(=O)NCc2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NCc1ccccn1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.4 %

Procedure:
11.7 g (0.85 mol) of potassium carbonate in solution in 86 ml of water are added to 11.5 g (0.43 mol) of 3-{[(pyridin-2-ylmethyl)amino]carbonyl}phenyl acetate (stage A) in solution in 340 ml of methanol. The mixture is stirred at ambient temperature for 3 hours and then concentrated to dryness. The residue is taken up in ethyl acetate and the product is neutralized with 85 ml of a molar solution of hydrochloric acid. The two phases are separated. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulphate. The solid obtained after concentration under vacuum is washed with ethyl ether and filtered. After drying, 6.3 g (65%) of a white solid are obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(=O)NCC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Reaction time: 17 h
Yield: 78.9 %

Procedure:
A mixture of 2-acetylaminomethylmorpholine (7.0 g), 4-fluorobenzyl chloride (12 g), potassium carbonate (56 g), potassium iodide (1 g), and methyl ethyl ketone (100 ml) is refluxed with stirring for 17 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is diluted with water and extracted with chloroform. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from toluene to give the title compound (9.3 g), mp 120°-122° C.