Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:13][CH3:14].P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:17])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2cc[nH]c(=O)c2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ccnc(Cl)c2cc1Br
Temperature: 25 °C

Procedure:
A mixture of the product from Step 2 (4.7 g, 18.5 mmol) in phosphorus oxychloride (30 mL) was heated to reflux for 2 hours and cooled to RT; the volatiles were evaporated; and the residue was partitioned between 3 M NaOH and DCM. The organic phase was dried over Na2SO4; the solvent was evaporated; and the solid was triturated with Et2O (20 mL) and filtered to give the title compound (3.75 g). LRMS ESI+ (M+H)+ 274.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[NH2:27][CH2:28][C@@H:29]([OH:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:27][CH2:28][C@H:29]([OH:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:5])[CH3:2]
Reactant: NC[C@@H](O)CN1CCOCC1
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(CCCNC[C@H](O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 45 °C
Yield: 45.6 %

Procedure:
5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and added with (R)-1-amino-3-morpholin-4-yl-propan-2-ol 78c (0.93 g, 5.8 mmol) to the solution at room temperature. Upon the completion of the addition, the reaction mixture was heated to 45° C. for 14 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped. The reaction solution was added with 15 ml of saturated brine, extracted with dichloromethane (20 ml×3), the combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (S)-5-[3-(2-hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 78d (600 mg, yield 72.5%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2].O.NN>C(Cl)Cl.CCO>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([CH2:24][NH2:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CN)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [(S)-5-benzyloxycarbonylamino-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pentyl]-carbamic acid tert-butyl ester (0.63 g, 1.27 mmol) in DCM (5.1 ml) and EtOH (5.1 ml) is treated with hydrazine hydrate (0.318 g, 6.35 mmol) and the reaction mixture is stirred at room temperature overnight. A white precipitate forms which is removed by filtration and washed with DCM (3×10 ml). The filtrate is concentrated in vacuo and redissolved in DCM (15 ml) and MeOH (2 ml). Undissolved material is removed by filtration and the filtrate is concentrated in vacuo. The resulting oily yellow solid is purified by chromatography on silica eluting with 10-50% MeOH in DCM (1% TEA) to afford ((S)-1-Aminomethyl-5-benzyloxycarbonylamino-pentyl)-carbamic acid tert-butyl ester as a clear oil; [M+H]+ 366
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[C:13]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=O)[CH3:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:14][CH2:13][C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: CC(=O)c1nccs1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: S=C(NN=CCc1nccs1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (50 mg, 0.273 mmol) and 2-acetylthiazole (41 mg, 0.33 mmol) similar to Example 3 and isolated as an off-white solid (30 mg, 37%). 1H NMR (DMSO-d6): 9.98 (s, 1H), 9.62 (s, 1H), 7.89 (m, 2H), 7.77 (m, 1H), 6.16 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.23 (m, 1H), 3.04 (s, 2H), 2.23 (s, 3H), 1.87-1.50 (m, 4H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH2:36][CH2:37][O:38][CH3:39])[C:27]=2[CH3:40])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.[CH2:48]([NH2:51])[CH2:49][CH3:50]>O1CCOCC1.O>[CH3:39][O:38][CH2:37][CH2:36][O:35][C:28]1[C:27]([CH3:40])=[C:26]([C:24]([C:21]2[CH:22]=[CH:23][C:14]([NH:13][C:5](=[O:11])[NH:51][CH2:48][CH2:49][CH3:50])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:25])[N:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[CH:33]2
Reactant: CCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCOc1c(C)c(C(=O)c2ccc(N)c(C(=O)OC)c2)n2ccccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCNC(=O)Nc1ccc(C(=O)c2c(C)c(OCCOC)c3ccccn23)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
0.108 g (0.37 mmol) of triphosgene diluted in 1 ml of dioxane is added, under an inert atmosphere at ambient temperature, to 0.2 g (0.52 mmol) of methyl 2-amino-5-{[1-(2-methoxyethoxy)-2-methylindolizin-3-yl]carbonyl}benzoate in 5 ml of dioxane. The reaction medium is stirred for 1 hour at ambient temperature and then 0.22 ml (1.57 mmol) of triethylamine and 0.09 ml (1.05 mmol) of n-propylamine are added. After stirring for 18 hours, the reaction medium is hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase obtained is dried over sodium sulphate, filtered, and concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 170 mg of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[C:31]([F:33])([F:32])[F:34])[C:6]=1[CH3:15]
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Example 99e) (0.03 g, 0.13 mmol) in DMF (1.0 ml) under an inert atmosphere of Argon is added sodium hydride (0.006 g of a 60% dispersion in mineral oil, 0.14 mmol). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (Example 95a) (0.067 g, 0.21 mmol) followed by sodium iodide (0.031 g, 0.21 mmol). Stirring is continued at 0° C. for 2 hours and then the reaction mixture is poured onto water (15 ml) and extracted with DCM (5 ml). The organic portion is separated and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the product which was further purified by trituration with ethyl acetate/iso-hexane to afford the titled product. (MH+ 475).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4]1=[O:17].C(N(CC)CC)C.[C:25](Cl)(=O)/[CH:26]=[CH:27]/[CH3:28]>O1CCCC1>[CH2:25]([NH:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4]1=[O:17])[CH:26]=[CH:27][CH3:28]
Reactant: NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: C/C=C/C(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC=CCNC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 13.6 g of 3-amino-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione hydrobromide in 100 ml of tetrahydrofurane are added, at 0° C., 12 ml of triethylamine. Then 6 ml of crotonyl chloride are added dropwise and the reaction mixture is stirred for a further 12 hours at room temperature. The solution is then filtered and the filtrate is concentrated. The residue is purified by column chromatography over silica gel with dichloromethane/petroleum ether (85:15) as eluant. The solvent is removed and the residue is recrystallised from ethyl acetate/petroleum ether. The colourless crystals melt at 107°-110° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:32]([C:31]3[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:23])=[O:22]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccs1)CC2

Procedure:
Light yellow solid. MS (ESI): 461.08 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), thiophene-2-sulfonyl chloride and 4-(trifluoromethoxy)aniline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[CH3:29][NH:30][C:31](=[S:34])[NH:32][NH2:33].O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:33][NH:32][C:31]([NH:30][CH3:29])=[S:34])=[O:23]
Reactant: CNC(=S)NN
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=S)NNC(=O)c1ccccc1-c1nc2ccc(F)cn2c1Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3.1 200 mg (0.533 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 56 mg (0.533 mmol) of 4-methyl-3-thiosemicarbazide and 125 mg (0.650 mmol) of DAPECI are dissolved in 1 ml of DMF and stirred at RT for 2 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 117 mg (47%) of 1-{2-[3-(2,6-dimethylphenylamino)-6-fluoro-imidazo[1,2-a]pyridin-2-yl]benzoyl}-4-methyl-3-thiosemicarbazide as solid; MS-FAB (M+H+)=463.7; Rf (HPLC, polar method): 1.69 min. This is employed in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[CH:7][N:6]([CH2:9]O)[N:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:13])=O>ClCCl>[ClH:13].[Cl:13][CH2:9][N:6]1[CH:7]=[N:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ncn(CO)n1
Solvent: ClCCl
Product: CC(C)c1ncn(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.28 g of 3-i-propyl-1H-1,2,4-triazole1-ylmethanol was dissolved to 20 ml of dichloromethane, and 2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure. Diethylether was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 1.58 g of 1-(chloromethyl)-3-i-propyl-1H-1,2,4-triazole hydrochloride.
Reaction SMILES: [CH2:1]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])[C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[Cu:14]=O>>[CH:1](/[C:2]([C:4]([F:5])([F:6])[F:7])=[O:3])=[C:8](\[C:10]([F:11])([F:13])[F:12])/[OH:9].[CH:1](/[C:2]([C:4]([F:5])([F:6])[F:7])=[O:3])=[C:8](\[C:10]([F:11])([F:13])[F:12])/[OH:9].[Cu:14]
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[Cu]
Product: O=C(/C=C(\O)C(F)(F)F)C(F)(F)F
Product: [Cu]

Procedure:
When HFAc is reacted with copper oxide, it yields Copper(II) hexafluoroacetylacetonate (Cu(II)(HFAc)2) according to the following reaction: Cu2O+2H+Hfac→Cu(HFAc)2+H2O
Reaction SMILES: [Br-:1].[CH2:2]([N+:9]1(C)[CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.CO.[H][H]>[C].[Pd].C(O)(=O)C>[BrH:1].[OH:19][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[OH:18])[CH2:17][N:9]([CH3:2])[CH2:10]2
Reactant: [H][H]
Reactant: C[N+]1(Cc2ccccc2)Cc2cc(O)c(O)cc2C1
Reactant: [Br-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Br
Product: CN1Cc2cc(O)c(O)cc2C1

Procedure:
1.0 g (2.97 mmol) of N-benzyl-5,6-dihydroxy-N-methylisoindolinium bromide obtained in Example 4 was dissolved in a solution comprising 10 ml of methanol and 10 ml of acetic acid, and 300 mg of a 10% palladium carbon catalyst was added thereto. Then, the catalytic reduction was conducted at 60° C. for 6 hours in a hydrogen gas stream. After filtering off the catalyst, the filtrate was evaporated to dryness under reduced pressure. To the residue, 10 ml of methanol was added, and the mixture was left to cool. The precipitated crystals were collected by filtration and washed with 10 ml of acetone to obtain 500 mg of the above identified compound as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:22])[F:21])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M306) (0.46 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (344 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21](=[O:20])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][NH:10]1
Reactant: NNc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2F)c1=O
Yield: 66.6 %

Procedure:
In the same manner as in Reference Example 63 and using (2,4-difluorophenyl)hydrazine•hydrochloride (5.1 g, 28 mmol), water (100 mL), potassium carbonate (8.6 g, 62 mmol) and diethyl ethoxymethylenemalonate (7.4 g, 34 mmol) as starting materials, the title compound (5.0 g, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:6]3[C:5]4[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Product: O=C1Nc2cc(Br)ccc2C1=Nc1ccc2cn[nH]c2c1
Yield: 48.1 %

Procedure:
The title compound (82 mg, 48%) was synthesized as a orange red solid according to the method described for Example A74 using 6-bromoisatin (113 mg, 0.5 mmol), 6-aminoindazole (73 mg, 0.55 mmol). 1H NMR indicated a 83:17 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H, NH), 10.93 (brs, 1H, NH), 8.09 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 7.05 (d, J=1.6 Hz, 1H), 6.92 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.77 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.27 (d, J=8.0 Hz, 1H); MS ESI 341.1 [M+H]+, calcd for [C15H9BrN4O+H]+ 341.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH:17]([CH3:19])[CH3:18].[CH2:22]([Mg]Cl)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1.CN1C(=O)CCC1>[CH2:16]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[N:7]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: O=S(=O)(Oc1cccc(Cl)n1)C(F)(F)F
Reactant: CCCCCCCCCCCCCC[Mg]Cl
Reactant: CC(C)C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1cccc(CC(C)C)n1
Reaction time: 0.05 h
Yield: 69.8 %

Procedure:
To a solution of 6-chloro-2-(trifluoromethanesulfonyloxy)pyridine (508 mg, 1.94 mmol) and Fe(acac)3 (34 mg, 0.096 mmol) in THF (8 mL) and NMP (2.3 mL) at 0° C. is slowly added a solution of isobutylmagnesium bromide (2M in Et2O, 1.1 mL, 2.2 mmol) causing a color change to yellow-brown. After stirring for 3 min at that temperature, a solution of C14H29MgCl (1M in THF, 2.3 mL, 2.3 mmol) is introduced via syringe causing an immediate color change to black-violet. After stirring for 5 min, an additional portion of Fe(acac)3 (20 mg, 0.057 mmol) and C14H29MgCl (1M in THF, 0.5 mL, 0.5 mmol) are added consecutively and the resulting mixture is stirred for another 15 min. Quenching of the reaction with brine followed by a standard extractive work up and flash chromatography (hexanes/ethyl acetate, 20/1) affords 2-(isobutyl)-6-(tetradecyl)pyridine as a colorless liquid (449 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.47 (t, J=8.3 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 2.71 (t, J=7.7 Hz, 2H), 2.58 (d, J=7.2 Hz, 2H), 2.07 (m, J=6.8 Hz, 1H), 1.68 (m, 2H), 1.20–1.35 (m, 22H), 0.87–0.92 (m, 9H). 13C NMR (75 MHz, CDCl3): 161.9, 160.9, 136.0, 120.4, 119.6, 47.6, 38.5, 32.0, 30.1, 29.80, 29.78, 29.75, 29.71, 29.6, 29.48, 29.47, 29.2, 22.8, 22.3, 13.9. MS m/z (rel. intensity) 331 (11, [M+], 316 (9), 289 (31), 176 (11), 162 (16), 149 (100), 120 (24), 107 (23).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1.ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1)(=[O:31])=[O:30]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C[C@H]1C[C@@H](COS(C)(=O)=O)OC(C)(C)O1
Reaction time: 2 h

Procedure:
2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (10.0 g), dichloromethane (150.0 mL), and triethylamine (17.0 mL) were added to a reactor. Methanesulfonyl chloride (4.7 mL) was added to the reaction mixture, which was then stirred for 2 hours. Water (200.0 mL) was added to the reaction mixture under stirring. The separated organic layer was washed with 0.5N hydrochloric acid solution (100.0 mL) and then concentrated under reduced pressure to obtain 2-[(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (13 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C(O)(C)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([NH:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Reactant: CN1CCN(CCCN)CC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CC(C)O
Product: CN1CCN(CCCNc2cc(Oc3ccc4c(c3)CCN4C(=O)Nc3cccc(C(F)(F)F)c3)ncn2)CC1

Procedure:
304 ring (0.70 mMol) of 5-(6-Chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (WO 03/099771; Stage 163), 477 μl (2.8 mMol) 1-(3-aminopropyl)-4-methyl-piperazine and a trace of Nal are heated in 10 ml isopropanol for 22 h at 50° C. Then the mixture is concentrated partially in vacuo. The residue is dissolved in EtOAc and NaHCO3 and the aqueous layer extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH/NH3conc. 9:1:0→90:10:1) gives the title compound: m.p.: 163° C.; MS: [M+1]+=556; TLC(CH2Cl2/MeOH/NH3conc. 90:10:2): Rf=0.29.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C@@H:14]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[OH-].[Na+]>CO.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:11][CH:10]=2)[C@@H:14]2[CH2:20][C:19]([CH3:21])([CH3:22])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])(=[O:25])=[O:26])=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(CCC(=O)O)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
3-(4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester (0.06 g, 0.11 mmol) was dissolved in methanol (4 ml) and treated with 1 N NaOH (0.2 ml) overnight. The mixture was diluted with water and the methanol removed under reduced pressure. The residue was acidified (KHSO4/K2SO4) and extracted with ethyl acetate (3×). The combined extracts were concentrated and the crude residue was purified using preparative RP(C18) chromatography: lyophilisate 15 mg; MS: m/e=491.1 (MH+).