Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[N:41]=[C:29]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([CH:40]=4)[CH2:36][CH2:37][C:38]=1[CH:39]=2)[N:28]=[CH:27][C:26]=3[Cl:42])=[O:18].[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:49]([C:50]([NH:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:24][C:25]3[N:41]=[C:29]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([CH:40]=4)[CH2:36][CH2:37][C:38]=1[CH:39]=2)[N:28]=[CH:27][C:26]=3[Cl:42])=[O:18])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)Nc1ccccc1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 38 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using 2-amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 38% yield. LCMS for C27H25ClN7O2 (M+H)+: m/z=514.2.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:21]([NH:27][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Product: CCCCCCNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 80 °C
Yield: 86 %

Procedure:
A mixture of compound 6 (23.5 mg, 0.059 mmol) and n-hexylamine (1 mL) was heated for 4.5 days at 80° C. After evaporation of volatiles, the residue was purified by preparative TLC (chloroform-methanol, 20:1) to give compound 14 (23.5 mg, 86.0%). 1H NMR (DMSO-d6) δ 0.84 (m, 3 H, CH3), 1.25 (m, 6 H, CH2), 1.45 (m, 2 H, CH2), 3.17 (m, 2 H, CH2), 3.54 (s, 3 H, 9-CH3), 4.58 (br s, 2 H, CH2), 6.32 (br s, 1 H, exchangeable with D2O, NH), 7.09 (pseudo t, J=7.8 and 7.6 Hz, 1 H, H-16), 7.35 (d, J=7.8 Hz, 1 H, H-17), 7.57 (d, J=7.7 Hz, 1 H, H-15), 7.66 (s, 1 H, H-13), 7.71 (s, 1 H, H-8), 7.82 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 27 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.5 ml of DMF was added 4.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. Pivaloyloxymethyl iodide (30 mg) was added, and the reaction mixture was stirred at −20-−30° C. for 1 hour. The reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of semi-saturated aqueous saline, and the mixture was stirred and separated. The organic layer was washed with semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to a volume of about 1 ml. It was purified by column chromatography on silica gel (ethyl acetate-ethyl acetate:methanol=97:3), and the solvent was concentrated under reduced pressure to a volume of about 0.5 ml and added dropwise to isopropyl ether. The resulting precipitate was collected by filtration, and desiccated under reduced pressure to give 17 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCCCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCCCCCCCCCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 9-phenylnonanoate (0.884 g, 3.37 mmol) in methylene chloride (10 ml) under argon at 0° was added diisobutylaluminum hydride (8.43 ml of a 1.0M solution). This mixture was warmed to room temperature and quenched with 10% aqueous hydrochloric acid. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol which was carried on without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:21]#[C:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][N:6]2[N:8]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1
Product: CC(C)c1cc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a brown solid, MS: m/e=245.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-isopropyl-pyrazolo[1,5-a]pyrimidine (example 38, step 1) and phenylacetylene.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][NH:13][C:14](=[S:16])[S-:15])=[CH:10][CH:9]=1.[NH4+]>CN(C)C=O>[C:5]([CH2:4][CH2:3][CH2:2][S:16][C:14](=[S:15])[NH:13][CH2:12][C:11]1[CH:17]=[CH:18][C:8]([Cl:7])=[CH:9][CH:10]=1)#[N:6]
Reactant: N#CCCCBr
Reactant: S=C([S-])NCc1ccc(Cl)cc1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CCCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To 37.5 g. of 4-bromobutyronitrile in 350 ml. of absolute dimethylformamide were added, while cooling with ice, 53.7 g. of ammonium (N-4-chlorobenzyl)dithiocarbamate and the mixture was stirred overnight at room temperature. After evaporation in vacuo, the product was taken up in ethyl acetate, washed with water, dried, concentrated and the residue crystallized from diethyl ether/diisopropyl ether, whereby 48.2 g. of 3-cyanopropyl(p-chlorobenzyl)dithiocarbamate having a melting point of 61°-63° C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:13]C1C=CC=CC=1.CC1C=C(C(F)(C(F)(F)F)C(F)(F)F)C=C(C)C=1N>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:13])=[O:8])([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Product: NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
3-nitro-benzoyl chloride was reacted with an aniline, that is 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine, to form a 3-nitro-benzamide, that is 3-nitro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide, and c) the 3-nitro-benzamide, that is 3-nitro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide, was reduced to afford the desired 3-amino-benzamide, that is 3-amino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide. Further 3-amino-benzamides were made, for example, by using a substituted 3-nitro-benzoic acid, such as 2-fluoro-3-nitro-benzoic acid, in step a) and/or a different aniline, such as 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoro-methyl-ethyl)-phenylamine, in step b). Whilst this three step synthesis gives satisfactory results in the laboratory a shorter route to 3-amino-benzamides is required if the carbamate insecticides or bisamide insecticides are to be manufactured on a commercial scale.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].Cl.[CH:27]1([NH:31][NH2:32])[CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20]1[N:31]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[N:32]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNC1CCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as orange oil. MS (ESI): m/z=438.3 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)C=C.[C:17]1(OC2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1>>[CH2:22]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[OH:4])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:17]=[CH2:18]
Reactant: C=CCOc1ccnc2ccc(OC)cc12
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cnc2ccc(OC)cc2c1O
Yield: 32 %

Procedure:
A solution of 4-allyloxy-6-methoxy-quinoline (4.0 g, 18.6 mmol, 1.0 eq) in diphenyl oxide (80 mL) is heated at 180° C. for 1 hour. The reaction mixture is then cooled down to room temperature before the addition of petroleum ether (100 mL). The resulting suspension is filtered to afford 3-allyl-6-methoxy-quinolin-4-ol as a light grey solid (1.3 g, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH-].[K+]>C(Cl)Cl.CN(C=O)C.CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cnccn2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(8-chloro-2-methyl 1,2,3,4 tetrahydro-pyrido (4,3-b) indol-5-yl)-2-pyrazin-2-yl-propan-2-ol (500 mg, 1.4 mmol) in DCM (8 mL) and DMF (2 drops) was stirred at 0-10° C. Thionyl chloride (0.5 mL, 7.0 mmol) diluted in DCM (8 mL) was added to the reaction mixture, which was stirred at RT for 1 h. The solvent was removed under vacuum to obtain the crude foamy solid. The solid was dissolved in NMP (6 mL) and the reaction mixture stirred for 5 min. Powdered KOH (551 mg, 9.83 mmol) was added to the reaction mixture and the mixture heated at 100° C. for 30 min. After completion of reaction, the reaction mixture was poured in water and extracted with EtOAc (100 mL×3). The organic layer was washed with water, concentrated under vacuum to obtain the crude product which was purified by reverse phase HPLC. 1H NMR (CDCl3, free base) δ (ppm): 8.80 (s, 1H), 8.58 (d, 1H), 8.50 (d, 1H), 7.62 (s, 1H), 7.40 (s, 1H), 7.15 (d, 1H), 7.05 (d, 1H), 3.70 (s, 2H), 2.82 (m, 4H), 2.58 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[O:7][CH:3]1[CH:2]([O:1][CH3:20])[CH2:6][O:5][CH2:4]1
Reactant: COc1ccc(C#N)cc1OC1COCC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OC1COCC1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
1.0 g (4.2 mmol) of 3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A15) in 5 ml of dimethylformamide is added dropwise under a nitrogen atmosphere to a solution of 140 mg (4.6 mmol) of 80% strength sodium hydride in 5 ml of dimethylformamide and the mixture is heated at 60° C. for 20 min. 315 μl (5.0 mmol) of methyl iodide, dissolved in 1 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 2 h, concentrated, treated with 20 ml of water and acidified with 2 N hydrochloric acid. After extraction with 3×30 ml of ethyl acetate, the combined organic phases are dried over magnesium sulfate, concentrated and the crude product is recrystallized from 10 ml of isopropanol. 760 mg of the title compound of m.p. 98-100° C. are obtained.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[S:30])=[CH:20]1.C(O[K])(C)(C)C.Cl>C1COCC1.CCOC(C)=O.O>[C:6]1([C:4]2[C:3](=[O:18])[NH:31][C:29](=[S:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: NC(=S)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NC(=S)C(c2c[nH]c3ccccc23)=C1c1cn2c3c(cccc13)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester (3.4 g, 14 mmol) and 2-(1H-indol-3-yl)-thioacetamide (2.9 g, 15 mmol) in anhydrous THF (34 mL) at −30° C. under N2 was added dropwise 1M tBuOK in THF (42 mL, 42 mmol). The reaction mixture was allowed warm to room temperature over 2 h. The reaction mixture was cooled to 0° C. and concentrated HCl (42 mL) added slowly. The mixture was allowed warm to room temperature with stirring over 1 h before being diluted with EtOAc and water. The organics were separated, washed with brine and evaporated to yield a dark residue. The residue was purified by column chromatography (SiO2, EtOAc/hexanes). 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-5-thioxo-1,5-dihydro-pyrrol-2-one was obtained as a dark foam (4.7 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[CH2:17]([O:19][CH2:20][CH2:21]Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:19][CH2:20][CH2:21][N:7]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6]1)[CH3:18]
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (WO00/24745, page 48, preparation 2) (2.0 g, 8.83 mmol) was added to a solution of 2-ethoxyethyl bromide (1.18 mL, 10.45 mmol) and potassium carbonate (1.32 g, 9.56 mmol) in N,N-dimethylformamide (35 mL) and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 100:0 to 70:30 to yield the ester product, 1.63 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.05 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.Br[CH2:9][CH2:10][Cl:11].BrCCBr>>[O:7]=[C:4]1[N:3]([CH2:9][CH2:10][Cl:11])[CH:2]=[N:1][CH:6]=[CH:5]1.[N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1
Reactant: ClCCBr
Agent: O=c1ccnc[nH]1
Solvent: BrCCBr
Product: O=c1ccncn1CCCl

Procedure:
When an equivalent amount of 4-pyrimidone is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19, 2-(1,6-dihydro-6-oxopyrimidin-1-yl)ethyl chloride is isolated after column chromatography (4-pyrimidone, Aldrich, 34%, B).
Reaction SMILES: [CH3:1][N:2]([C:13]1[N:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11]O)[CH2:5][CH2:4]1.CS([Cl:24])(=O)=O.N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Cl:24][CH2:11][C:10]#[C:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[C:13]2[N:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH2:4][CH2:5]1
Reactant: Cc1ccc(N(C)[C@H]2CC[C@H](C#CCO)CC2)nn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(N(C)[C@H]2CC[C@H](C#CCCl)CC2)nn1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 0.246 g (0.95 mmol) of trans-3-{4-[Methyl-(6-methyl-pyridazin-3-yl)-amino]-cyclohexyl}-prop-2-yn-1-ol in 7 ml CH2Cl2 was treated at 0° C. with 0.081 ml (1.04 mmol) methanesulfonylchloride and 0.17 ml (1.42 mmol) 2,6-lutidine. The reaction was stirred for 22 h at room temperature, water (1 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 0.285 g of crude trans-[4-(3-Chloro-prop-1-ynyl)-cyclohexyl]-methyl-(6-methyl-pyridazin-3-yl)-amine, MS: 278 (MH+, 1Cl).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[C:15](=[N:18]/[S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])/[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CC/C(=N\S(=O)C(C)(C)C)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 6 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-prop-(E)-ylidene]-amide (2.00 g, 5.24 mmol) in THF was added a 1 M solution of L-Selectride (5.27 mL, 5.27 mmol) in THF. After 6 hours, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-40% ethyl acetate in heptane. The major fraction (with one diastereomer) were combined and the solvent was removed in vacuo to afford 2-methyl-propane-2-sulfinic acid {(S)-1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propyl}-amide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:9]=[C:10]([C:20]#[N:21])[NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH3:22][C:23]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([CH3:32])[O:25][N:24]=1.O>C(#N)C>[Cl:7][C:8]1[N:9]=[C:10]([C:20]#[N:21])[N:11]([S:28]([C:27]2[C:23]([CH3:22])=[N:24][O:25][C:26]=2[CH3:32])(=[O:30])=[O:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: Cc1ccc(-c2[nH]c(C#N)nc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2c(Cl)nc(C#N)n2S(=O)(=O)c2c(C)noc2C)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 47.8 %

Procedure:
2.0 g (15 mmol) of potassium carbonate are added to a solution of 2.2 g (10 mmol) of 4-chloro-5-(4-tolyl)-imidazole-2-carbonitrile in 30 ml of acetonitrile, and the mixture is stirred at 20° C. for 10 minutes. The mixture is subsequently admixed with 1.9 g (10 mmol) of 3,5-dimethylisoxazole-4-sulphonyl chloride and stirred at 20° C. for 4 hours. The reaction mixture is then poured into 150 ml of water and extracted with 50 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The residue that remains is chromatographed over silica gel using methylene chloride as mobile phase. Concentration of the eluate under reduced pressure gives 1.8 g (50% of theory) of 4-chloro-1-(3,5-dimethylisoxazol-4-yl-sulphonyl)-5-(4-tolyl)-imidazole-2-carbonitrile in the form of a colourless solid of melting point 103 to 108° C.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[NH:14][C@H:15]([CH3:30])[C:16]([NH:18][CH:19]2[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[NH:14][C@@H:15]([CH3:30])[C:16]([NH:18][CH:19]2[CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CNC1

Procedure:
To a solution of the compound (846 mg), which had been obtained in (1), in anhydrous dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation. Infrared absorption spectrum (Liquid film) νmax cm-1 : 3213, 1758, 1677, 1610, 1600, 1560, 1526.