Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCN1CCCC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 1-(3-aminopropyl)pyrrolidin-2-one according to general procedure 1 providing the intermediate (150 mg, 58%) as a white solid; Rf=0.58 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.53 (t, J=7.1 Hz, 2H), 3.43-3.38 (m, 4H), 2.39 (t, J=8.0 Hz, 2H), 2.08 (quin, J=7.6 Hz, 2H), 1.94 (quin, J=6.9 Hz, 2H); ES-MS: (M+H)=338, 340 m/z.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][C:6](=[O:8])[CH3:7].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[C:15]([CH:20]=O)[CH2:16][O:17]2)=[CH:12][CH:11]=1>CO>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[S:4][C:5]([C:6](=[O:8])[CH3:7])=[CH:20][C:15]=3[CH2:16][O:17][C:18]=2[CH:19]=1
Reactant: CC(=O)CS
Reactant: O=CC1=C(Cl)c2ccc(Br)cc2OC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc2c(s1)-c1ccc(Br)cc1OC2
Reaction time: 0.25 h

Procedure:
To a solution of sodium methoxide (5.57 g, 103 mmol) in 250 ml of methanol at 0° C., mercaptoacetone (5.11 g, 57 mmol) was added portion-wise, and after 15 min., 7-bromo-4-chloro-2H-chromene-3-carbaldehyde (1a) (14 g, 52 mmol) was added to it portion-wise with stirring. After the addition, the ice bath was removed and the product gradually started precipitating out as a yellow solid. Stirring was continued for another 3 h, after which water was added to quench the reaction and the methanol was removed under vacuum. Addition of more water yielded the title compound as a yellow solid (1b) which was filtered and dried (14.1 g, 78%). m/z 308.9 (79Br) & 310.9 (81Br).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[NH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH3:26])=[CH:21][N:20]=1)[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:25][C:23]1[C:22]([CH3:26])=[CH:21][N:20]=[C:19]([N:17]2[C:5](=[O:6])[C:4]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][NH:18]2)[CH:24]=1
Reactant: Cc1cnc(NN)cc1C
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cnc(-n2[nH]cc(-c3cccnc3)c2=O)cc1C
Temperature: 25 °C

Procedure:
220 mg (1.0 mmol) of the compound from Example 2A are initially charged in 5 ml of ethanol. 137 mg (1.0 mmol) of the compound from Example 21A and 38 mg (0.2 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, and the solid formed is filtered off, washed with tert-butyl methyl ether and dried under high vacuum. This gives 28 mg of the title compound. The mother liquor is put aside and used for preparing the hydrochloride (see Example 87).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Si:23]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=[C:2]([Cl:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Cl)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (142 mg, 0.671 mmol, Example 121, Step A) in methylene chloride (1.0 mL) at 0° C. was added 1H-imidazole (55 mg, 0.80 mmol) followed by tert-Butylchlorodiphenylsilane (190 μL, 0.74 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The reaction was stirred with warming to room temperature for 64 hours. The reaction mixture was diluted with diethyl ether and was washed with water followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-4% EtOAc in hexanes afforded product as a white solid (0.20 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.58 (m, 4H), 7.55-7.34 (m, 8H), 4.77 (s, 2H), 1.12 (s, 9H); 19F NMR (282 MHz, CDCl3) δ−68.49 (s); LCMS (M+H)+: 450.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH3:21]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To 1.24 g (4.5 mmol) of the compound (189) obtained in Example 62, 8 ml (87 mmol) of dimethylsulfate was added, and the solution was heated at 120° C. for 3 hours. After air-cooling, the solution was added to 70 ml of ice/water to which 12 g (87 mmol) of anhydrous potassium carbonate was added, and the solution was stirred for 1 hour. The solution was extracted with 100 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel 40 g, eluent solvent; chloroform:methanol=100:1) to obtain 571 mg of the subject compound (190) in a 46% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:14][CH3:15])=[C:7](C(O)=O)[NH:8]2)=[CH:4][C:3]=1[F:16].[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:14][CH3:15])=[CH:7][N:8]2[CH2:19][C@H:20]([OH:21])[CH3:22])=[CH:4][C:3]=1[F:16]
Reactant: C[C@@H]1CO1
Reactant: CCc1c(C(=O)O)[nH]c2cc(Cl)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cn(C[C@@H](C)O)c2cc(Cl)c(F)cc12
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 1.16 g of 6-chloro-5-fluoro-3-ethyl-indole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 24 ml of tetrahydrofuran. 180 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.5 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 112 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:1). 0.97 g (79%) of (R)-1-(6-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol was obtained as pale brown crystals with m.p. 112°-114°.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[NH2:22][CH2:23][C@@H:24]([OH:27])[CH2:25][OH:26].C(N(CC)CC)C>CCO>[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[N:22]([CH2:23][C@@H:24]([OH:27])[CH2:25][OH:26])[CH:2]=[C:3]3[C:4]=2[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]3[CH3:9])[CH:19]=[CH:18][CH:17]=1
Reactant: NC[C@@H](O)CO
Reactant: Cn1c(CBr)c(C(=O)c2cccc(Cl)c2)c(=O)n(C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
A mixture of 6-(bromomethyl)-5-(3-chlorobenzoyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2 g, 5.38 mmol), (R)-3-aminopropane-1,2-diol (0.490 g, 5.38 mmol) and triethylamine (0.750 ml, 5.38 mmol) in EtOH (17.94 ml) was heated under microwave irradiation at 100° C. for 1 hour. The mixture was evaporated under vacuum and the residue partitioned between DCM (20 mL) and 1M HCl (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL). The organic phase was passed through a hydrophobic frit and evaporate under vacuum to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](#[N:18])C>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:16]#[N:18])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cc(CBr)ccc1-c1ccccc1
Reactant: CC#N
Product: N#CCc1ccc(-c2ccccc2)c(F)c1

Procedure:
The crude monobromide prepared in Example 4 was refluxed with 100 ml of EtOH and 6.9 g (0.14 mol) of NaCN for one hour. Most of the EtOH was then removed in a rotary evaporator at reduced pressure and the resulting residue was partitioned between H2O and Et2O. The Et2O phase was dried over MgSO4 and concentrated to leave 19.3 g of brown semi-solid material. Analysis of this material by NMR showed that it contained the acetonitrile and only trace amounts of the monobromide. The crude acetonitrile material was stirred all night in petroleum ether and then filtered. The product was collected as 13.2 g of brown solid that contained about 5% of the starting material according to GC analysis. Concentration of the petroleum ether solution gave 4.9 g of orange liquid that contained mostly the starting material and some of the product acetonitrile. The yield of the 95% pure acetonitrile based on unrecovered fluoride (3) was about 70-80%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([OH:10])=[N:8][CH:9]=1.[CH3:14]I>O>[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7](=[O:10])[N:8]([CH3:14])[CH:9]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1cc(Cl)cc([N+](=O)[O-])c1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
NaH (52.6 mmol) was slowly added at 5° C. to a solution of 5-chloro-2-hydroxy-3-nitropyridine [21427-61-2] (43.8 mmol) and the mixture was stirred at 5° C. for 30 min. Methyl iodide (65.7 mmol) was added and the mixture was stirred at rt for 20 h. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic phases were washed successively with H2O and brine, dried (Na2SO4), filtered and concentrated to afford the title compound. ESI-MS: tR=0.55 min, [M+H]+ 189/191 (LC-MS 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:21])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)F)c1ccccc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24k (125.8 mg, 0.50 mmol) was added 1.25 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (225 μL, 2.5 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (40 μL, 0.5 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 115.3 mg of a mixture of 24k and 25k as an off-white solid. FTIR (film) 1849.3 cm−1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH3:27])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH3:27])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CC1CCCN1c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1CCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
Sodium triacetoxyborohydride (2.09 g) was added to a solution of 3-chloro-5-(2-methylpyrrolidin-1-yl)pyrazine-2-carbaldehyde (1.49 g), N-benzylethanolamine (1.19 g) and acetic acid (1.13 mL) in acetonitrile (12 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→50% ethyl acetate/hexane) to give the title compound (1.82 g, 76%) as a pale-yellow oil.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:34][O:35][C:36](=[O:45])[CH2:37][CH:38]([NH2:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41].CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:44][CH:38]([CH2:37][C:36]([O:35][CH3:34])=[O:45])[CH2:39][C:40]([O:42][CH3:43])=[O:41])=[O:17])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(N)CC(=O)OC
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC(CC(=O)OC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
4-[[4-(aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (4.6 g, 17 mmol) was added to dry DMF (225 ml) followed by N-methylmorpholine (1.2 g, 17 mmol) and isobutyl chloroformate (2.3 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Dimethyl-3-aminoglutarate (3.0 g, 17 mmol) was added followed by dimethylaminopyridine. After 1 hr, the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.5 g of a white solid: 1H NMR (d6 -DMSO) δ2.37 (t, 2H, J=7.3 Hz), 2.55 (m, 2H), 2.57 (t, 2H, J=7.1 Hz), 3.57 (s, 6H), 4.35 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1H,J=8.1 Hz), 9.1(bs, 2H), 9.19 (bs, 2H), 10.42 (s, 1H); MS (FAB) m/z 393.2 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[O:20][CH2:21][S:22](=[O:32])(=[O:31])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].CCOCC>CO>[ClH:33].[CH2:24]([N:23]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:19]=2[O:20][CH2:21][S:22]1(=[O:32])=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCS(=O)(=O)N3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=S1(=O)COc2c(N3CCNCC3)cccc2N1Cc1ccccc1
Temperature: 100 °C

Procedure:
4-(1-Benzyl-2,2-dioxo-2,3-dihydro-1H-benzo[4,2,1]oxathiazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL methanol and 1 mL of 2N ethanolic HCl was added. The solution is heated at 100° C. for 30 minutes, at which time was added approximately. 2 mL Et2O. On cooling to room temperature, 30 mg of 1-benzyl-5-piperazin-1-yl-1H-benzo[4,2,1]oxathiazine 2,2-dioxide hydrochloride precipitated as a white solid (61%). (M+H)+=360.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([NH:21][C:22](=[O:24])C)[CH:19]=[CH:20][C:13]=2[NH:12][C:11](=[O:25])[CH2:10]1.CO.O=S(Cl)Cl.[CH2:33]([N:40]=C=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO.Cl>[CH2:33]([NH:40][C:22](=[O:24])[NH:21][C:18]1[CH:19]=[CH:20][C:13]2[NH:12][C:11](=[O:25])[CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:26])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)CCCCCN1CC(=O)Nc2ccc(NC(C)=O)cc2C1=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: O=C(O)CCCCCN1CC(=O)Nc2ccc(NC(=O)NCc3ccccc3)cc2C1=O
Reaction time: 18 h
Yield: 19.5 %

Procedure:
80 mg (0.22 mmol) 6-(7-acetylamino-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-hexanoic acid methyl ester was dissolved in 1 ml MeOH/HCl (freshly prepared from 10 ml MeOH and 1 ml SOCl2). The solution was stirred for 18 h and concentrated in vacuo. The residue was taken up in 2 ml of THF/MeOH (1: 1) and 0.5 ml 1N aqueous NaOH was added. After stirring for 16 h at 22° C. the mixture was neutralised by addition of solid carbon dioxide, and the solvents were evaporated. The residue was taken up in DMF (2.5 ml) and 0.032 ml benzylisocyanate (0.26 mmol) was added. The mixture was shaken at 45° C. over night and evaporated. The crude product was purified by preparative HPLC to give 6-[7-(3-benzyl-ureido) -2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-hexanoic acid (19 mg, 0.043 mmol): MS (ISN) 437(M−H)−.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][NH:10][NH2:11])[CH2:2][CH2:3][CH3:4].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:11][N:10]([CH2:9][C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)[C:18](=[O:17])[CH:19]=1
Reactant: CCCCOc1cccc(CNN)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCOc1cccc(Cn2[nH]c(N)cc2=O)c1
Reaction time: 2 h

Procedure:
18 g of 3-n-butoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 14.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 180 ml of ethanol. After stirring for 2 hours, the mixture was left to stand overnight. The compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 110°, 8 g (33%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:20][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)[CH:7]=2)=[C:14]([CH3:15])[N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=1
Reactant: CC(=O)Nc1cc(C)c(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of N-(5-((2-chloropyridin-4-yl)oxy)-4,6-dimethylpyridin-2-yl)acetamide (598 mg, 2.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (554 mg, 2.66 mmol), K2CO3 (850 mg, 6.15 mmol) and Pd(PPh3)4 (118 mg, 0.102 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford crude N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (100% yield assumed) which was used without further purification. MS (ESI) m/z: 338.1 (M+H+).
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19](O)[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)[Cl:27]>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([Cl:27])[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(=O)OCc1cc(Cl)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 40 ml of N,N-dimethylaniline, and 35 g of 5-acetoxymethyl-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50° C. for one hour. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, removing a solvent, an oily product was obtained. This was applied to a silica gel column chromatography (eluent: chloroform) and fractions containing the title compound were condensed to obtain an oily product. This was allowed to stand to cool and crystallized to obtain 31 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([F:12])[C:7]([CH2:8][OH:9])=[C:6]([F:13])[CH:5]=1)[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[C@H:23]([CH2:30][CH3:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:13])[C:7]([CH2:8][O:9][C:27]([N:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])[CH2:22][C@H:23]2[CH2:30][CH3:31])=[O:28])=[C:10]([F:12])[CH:11]=1)[CH3:2]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: CCOc1cc(F)c(CO)c(F)c1
Product: CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 81 %

Procedure:
This compound was prepared from 4-ethoxy-2,6-difluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (478 mg; 81%); MS (ISP): 429.6 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 28 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone, 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (28%).