Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[Cl-:15].[Ca+2].[Cl-].O>CS(C)=O>[Cl:15][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: [Cl-]
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Agent: [Ca+2]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c(C(F)(F)F)ccc(F)c1Cl
Temperature: 145 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
To a solution of 50.9 g of 2,3-difluoro-6-trifluoromethylbenzonitrile in 240 ml of dimethyl sulfoxide (DMSO) was added 53.3 g of calcium chloride and the mixture was stirred for 6 hours at a temperature of from 140 to 150° C. After cooling, the reaction mixture was further added with 240 ml water and extracted with 240 ml and 100 ml hexane twice. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent therein was distilled under reduced pressure. The crude product obtained was distilled under reduced pressure to obtain 38.9 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[N:6]=1)=O.[NH3:28]>CO>[C@@H:10]1([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:28])=[O:2])=[N:6]2)[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]1[OH:12]
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Yield: 90 %

Procedure:
A solution of 1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (10.0 g., 26.0 mmole) in methanol (70 ml.) saturated at 0° with anhydrous ammonia was kept in a sealed pressure flask at 25° for 18 hrs. The product was crystallized from ethanol to give 1-(β -D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (5.70 g., 90.0%).
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:20]1[C:21]2[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=2[N:23]=[CH:24][N:25]=1>>[N:1]1([CH2:5][C@H:6]([NH:7][C:20]2[C:21]3[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=3[N:23]=[CH:24][N:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cncc2c(O)ncnc12
Reactant: N[C@@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Product: NC(=O)c1cncc2c(N[C@@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 19 was prepared following general synthetic scheme 7 wherein (R)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanamine was reacted with 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide to give the title compound as an off-white solid. LC-MS [451 (M+1)], 1H NMR (400 MHz, Chloroform-d) δ 10.43 (s, 1H), 9.75 (s, 1H), 9.59 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.48 (d, 2H), 6.12 (s, 1H), 5.18 (d, 1H), 3.25 (dq, 4H), 3.05-2.89 (m, 2H), 2.14 (p, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23][OH:24])=[CH:15]3)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29][CH3:30])=[O:28])[C:7]1=[O:31].CCN(CC)CC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23][O:24][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:15]3)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29][CH3:30])=[O:28])[C:7]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCO)n2C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Temperature: 0 °C
Yield: 98.7 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(2-(2-hydroxyethyl)-1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.142 g, 2.26 mmol) in DCM (10 mL) was added NEt3 (0.45 mL, 3.23 mmol) and mixture was cooled to 0° C. Methanesulfonyl chloride (0.22 mL, 2.84 mmol) was added dropwise and reaction mixture was stirred at 0° C. 15 min. LC/MS indicated complete consumption of the starting material. Reaction was diluted with DCM (20 mL) and washed with H2O (10 mL). Organic phase was dried over Na2SO4 and solvent was removed under reduced pressure. Methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.30 g) was obtained in nearly quantitative yield as yellow solid and was pure enough to be used in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][OH:22])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(Cl)(Cl)Cl>Cl>[CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][O:22][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(C2C(CO)CC(=O)N2Cc2ccccc2)c1
Agent: Cl
Agent: [K]
Solvent: ClC(Cl)Cl
Product: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
To 21.4 gm. of 1-benzyl-4-hydroxymethyl-5-(3methoxyphenyl)pyrrolidin-2-one in 40 ml. of potassium dried pyridine was slowly added at -4° to -7°, 14.4 gm of p-toluenesulfonyl chloride. The reaction mixture was stirred for 3 hours at 15° and then diluted with 180 ml of 10% hydrochloric acid. The gum was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to provide 24.6 gm. of the desired products as an oil. ir (CHCl3): 1165-1195 cm-1 ; 1335-1375 cm-1
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[CH2:20]([O:22][C:23](=[O:47])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](Br)[CH:41]=2)[CH:34]=1)[NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH3:21].C(OCC)(=O)C>O1CCOCC1>[CH2:20]([O:22][C:23](=[O:47])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[CH:45]=2)[CH:34]=1)[NH:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH3:21]
Reactant: CCOC(=O)[C@H](Cc1cccc(Oc2cccc(Br)c2)c1)NC(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1cccc(Oc2cccc(-c3ccncc3)c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A solution of 4-(tributylstannyl)pyridine (288 mg, 0.782 mmol) in degassed 1,4-dioxane (1 ml) and tetrakis(triphenyl-phosphine)palladium (46 mg, 0.04 mmol) were added in turn to a solution of 3-(3-bromophenoxy)-N-trifluoroacetyl-L-phenylalanine ethyl ester (360 mg, 0.782 mmol) in degassed 1,4-dioxane (6 ml) at room temperature and the mixture was stirred under heating for 8 hrs. After the mixture was cooled to room temperature, ethyl acetate was added thereto and the mixture was washed with saturated sodium fluoride solution, water and brine in turn and then dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1) to give N-trifluoroacetyl-3-[3-(4-pyridyl)phenoxy]-L-phenylalanine ethyl ester (235 mg, 66%) as colorless resinous substance.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][N:13]=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28]>C(#N)C>[CH3:29][CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([NH:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][N:13]=1)=[O:41])[CH3:28]
Reactant: CCCCCCCCCCCCCc1nnc(N)o1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCCc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)o1
Reaction time: 18 h

Procedure:
Triethylamine (1.67 g, 0.017 mol) was added to a solution of the compound prepared in Step 2 above (4.0 g, 0.015 mol) in acetonitrile (200 mL) and the mixture refluxed for 30 minutes or until solution becomes homogeneous. 2,6-Diisopropylphenyl isocyanate (3.71 g, 0.018 mol) was then added and reflux continued for 18 hours. The mixture was allowed to cool, concentrated, diluted with water (20 mL), filtered, and the solid columned on silica gel, eluting with 20% ethyl acetate in hexanes (loaded in chloroform) to give 0.54 g of a solid; m.p 114°-116.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[CH2:15][O:14][C:13]2[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:12]=2[Cl:11])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:14]([CH3:31])=[C:13]([CH3:32])[N:12]=1>COCCOCCOC.C(OCC)(=O)C>[CH3:32][C:13]1[C:14]([CH3:31])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
Under a nitrogen atmosphere, diglyme (25 mL) was added to sodium hydride (1.81 g, 45.2 mmol), which is available as a 60% dispersion in mineral oil, and the mixture was cooled to 5° C. A solution of phenol (4.54 g, 48.2 mmol) in diglyme (50 mL) was added dropwise over a period of 15 minutes. The reaction became homogeneous after 15 minutes. A solution of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine (10.15 g, 30.14 mmol) was added, and the reaction was heated at 160° C. for 13 hours. An analysis by HPLC indicated the presence of starting material. Additional phenol (3.12 g, 33.2 mmol) was added to 60% sodium hydride (1.24 g, 31.1 mmol) in diglyme, and the mixture was stirred until it became homogeneous. This solution was added to the cooled reaction flask, and the reaction was heated at 160° C. for 9.5 hours. The reaction was allowed to cool to room temperature, and the volatiles were removed under reduced pressure to provide a black oil. The oil was dissolved in ethyl acetate, and the solution was washed with 1 N potassium hydroxide (3×) and brine (3×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 80:20 ethyl acetate:hexane) to provide 2.47 g of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27].[CH:30]1([NH:36][C:37]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:42]2[CH2:43][CH2:44][CH:39]([C:37]([NH:36][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:38])[CH2:40][CH2:41]2)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(N3CCC(C(=O)NC4CCCCC4)CC3)c(F)cc2c1=O
Yield: 10.5 %

Procedure:
200 mg (0.44 mmol) of the compound of Example 70A and 138 mg (0.66 mmol) of 4-(cyclohexylamino)carbonylpiperidine (for preparation see WO 2003031397) are heated with 91 μl (0.66 mmol) of triethylamine in 4 ml of DMSO at 120° C. for 7 h. After cooling, the entire reaction mixture is separated by preparative HPLC (method 6). 30 mg of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH3:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:13])=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@@H:23]2[CH2:27][OH:28])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: Cc1c(C#N)cccc1C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1C(=O)CN1CCN(C(=O)OC(C)(C)C)C[C@@H]1CO
Temperature: 25 °C

Procedure:
To a solution of 3-(chloroacetyl)-2-methylbenzonitrile (1.7 g, 8.8 mmol) in THF (17.6 mL) was added (R)-4-N-boc-2-hydroxymethyl-piperazine (2.279 g, 10.54 mmol) and DIPEA (3.07 mL, 17.56 mmol) at rt. The reaction mixture was stirred at rt over the weekend. After concentration, the residue was partitioned between EtOAc and aqueous NaHCO3 (saturated). The aqueous layer was extracted with EtOAc (2×). The combined organic phase was washed with brine, dried over anhydrous MgSO4, and filtered. Concentration was followed by purification by prep TLC (silica gel; 10% MeOH/DCM) to give the title compound: LC/MS (M+1)+=374.14
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH3:31])=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH3:31])=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)OC)cc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
After adding methanol (14 ml) and a 2N sodium hydroxide aqueous solution (7 ml) to methyl 4-(3-chloro-4-(((methylamino) carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate (1.31 g, 3.15 mmol), the mixture was stirred at 60° C. for 30 minutes. The reaction solution was cooled to room temperature, 2N hydrochloric acid was added for neutralization, the methanol was distilled off, and the precipitated white crystals were filtered out, thoroughly washed with water and dried at 60° C. to obtain the title compound (1.26 g, 3.15 mmol, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([CH2:7]Cl)=[CH2:6])[CH3:2].[CH2:10]([O:12][P:13]([CH2:18][CH:19]([CH2:29][OH:30])[CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11].C(N(CC)CC)C>C1COCC1>[CH2:23]([O:22][P:21]([CH2:20][CH:19]([CH2:29][O:30][CH2:7][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH2:6])[CH2:18][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])(=[O:28])[O:25][CH2:26][CH3:27])[CH3:24]
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Reactant: C=C(CCl)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(COCC(CP(=O)(OCC)OCC)CP(=O)(OCC)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 45 h
Yield: 47.5 %

Procedure:
Ethyl-2-(chloromethyl)-acrylate (3.86 g, 26.0 mmol, 1.5 eq.) was added to a solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (6.0 g, 17.3 mmol) and triethylamine (3.62 ml, 26 mmol, 1.5 eq.) in anhydrous THF (30 ml), and the reaction mixture was stirred for 45 h at 70° C. After concentrating in vacuo deionized water (50 ml) was added and the obtained solution was extracted with ethylacetate (3×50 ml). The combined organic phases were dried with anhydrous sodium sulphate. After removal of the solvent under reduced pressure the obtained crude product was purified by column chromatography (eluent: ethylacetate/methanol 98:2). 3.77 g (48% yield) of the product was obtained as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:19]=4[S:20][C:3]=1[C:4]=23.Br.[Br:28][CH2:29][CH2:30][NH2:31]>CCO>[BrH:28].[CH2:16]([N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:29][CH2:30][NH2:31])=[C:3]3[S:20][C:19]4[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:17]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1c(OC)cccc1-2
Reactant: NCCBr
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1c(OC)cccc1-2
Yield: 34.2 %

Procedure:
Reaction of a solution of 3.5 g (0.0095 mol) of 5-amino-N,N-diethyl-7-methoxy-2H[1]benzothiopyrano-[4,3,2-cd]indazole-2-ethanamine and 5.8 g (0.0283 mol) of 2-bromoethylamine, hyrobromide, in 30 ml of EtOH as described in Example 38 gave 1.6 g of product.
Reaction SMILES: [Li+].[Cl-].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [Li+]
Product: C=CCc1cncc(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with i-PrMgCl.LiCl (1 mL, 1.05 M in THF, 1.05 mmole), the reaction mixture was cooled to −15° C. and 3,5-dibromopyridine (236.9 mg, 1 mmole) was then added at one portion. The temperature than increased till −10° C. and the Br/Mg-exchange was complete after 15 min (checked by GC analysis of reaction aliquots, conversion more than 98%), allyl bromide (140.6 mg, 1 mmole) was added. The reaction mixture was stirred for 1 h at −10° C. and was then quenched with sat. NH4Cl solution (2 mL). The aqueous phase was extracted with ether (3×4 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (dichloromethane) yielding the 3-allyl-5-bromopyridine (2ca) as a colourless oil (184.2 mg, 93%). 1H-NMR (CDCl3, 200 MHz): δ=8.48 (d, J=2.2 Hz, 1H); 8.32 (d, J=1.6 Hz, 1H); 7.61 (dd, J=2.2 Hz, J=1.6 Hz, 1H); 5.89-5.68 (m, 1H); 5.08-5.01 (m, 1H); 3.32 (brd, J=6.8 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([C:25]([OH:27])=O)[N:19]=[N:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([C:25]([NH:34][CH:32]3[CH2:33][CH2:31]3)=[O:27])[N:19]=[N:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.3 %

Procedure:
1-{4-[(Benzylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (507 mg, 1.39 mmol) obtained in Example 58b), HOBt (95 mg, 0.696 mmol, 0.5 eq.) and cyclopropylamine (0.129 ml, 1.81 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (327 mg, 1.67 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (1:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (520 mg, 1.29 mmol, 92.7%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:14](OCC)(=[O:16])[CH3:15].C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[C:6]([NH:7][C:14](=[O:16])[CH3:15])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: CCOC(C)=O
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A 100 mL three-neck round bottom flask was charged with 3-chloro-1(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). sodium bicarbonate (1.08 g, 12.9 mmol) was added, followed by dropwise addition of acetic anhydride (0.629 g, 6.17 mmol) at <20° C. The reaction was stirred at 20° C. for 2 hours to afford a suspension, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the resulting suspension was filtered. The solid was rinsed with water (10 mL) followed by methanol (5 mL). The solid was further dried under vacuum at 20° C. to afford the desired product as a white solid (0.804 g, 66%): mp 169-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.05 (dd, J=2.8, 0.8 Hz, 1H), 8.82 (s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.20 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.54, (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 168.12, 147.46, 139.42, 135.46, 133.60, 125.47, 124.21, 122.21, 120.16, 22.62; EIMS m/z 236 ([M]+).