Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:43][N+:44]#[C-:45])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]3[C:9]([C:12]4[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=4)=[CH:10][N:11]=[C:5]3[CH:4]=2)=[CH:45][N:44]=[CH:43]1
Reactant: O=Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnco4)ccn23)c1
Yield: 37.4 %

Procedure:
A solution of 1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (15 mg, 0.04 mmol), potassium carbonate (11 mg, 0.08 mmol) and TosMic (9.7 mg, 0.05 mmol) were heated in MeOH (2 ml) at 80° C. for 3 h. The reaction mixture was purified using a C18 SPE cartridge, washing with water and eluting the desired compound with MeOH. Removal of the solvent in vacuo afforded the title compound (6 mg). MS: [M+H]+=402
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O.O1CC[CH2:42][CH2:41]1>C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:41][CH3:42])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
1.3 mL (1.3 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.44 g (0.86 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 6 hours. After cooling, the reaction is worked up by addition of 3 mL (3 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.33 g (78%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a cream-colored solid with a melting point of 103° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40]C3CCCCO3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:38]1[N:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:48])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]5[CH2:15][CH2:16][O:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[N:35]=[N:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-morpholin-4-yl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M1) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (51 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:16]=O)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].[C:23]1([CH3:29])C=CC=C[CH:24]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH:29]3[CH2:23][CH2:24]3)[NH:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccccc1
Reactant: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Reactant: CS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Titanium isopropoxide (1.16 mL, 3.96 mmol) was added to a mixture of 2-Chloro-4-(5-formyl-pyridin-3-yl)-benzonitrile (480 mg, 1.98 mmol) and methanesulfonamide (188 mg, 1.98 mmol) in toluene (15 mL) at room temperature. The resulting mixture was refluxed for 2 h. After concentration, the residue was dissolved in THF (10 mL) and cooled to −40° C. A solution of c-PrMgBr (0.5 M in THF, 11.9 mL, 5.93 mmol) was added dropwise and the resulting mixture was stirred at −36° C. for 1 h. The reaction was quenched by addition of saturated NH4Cl solution. The resulting mixture was filtered, and the organic layer was separated. After concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-3%) to give N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)methanesulfonamide (351 mg, 49%); ESI-MS m/z: 362 [M+1]+, 1HNMR (MeOD, 400 MHz) δ 8.83 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.24 (t, J=2.0 Hz, 1H), 7.93 (4H, s), 3.96 (d, J=9.2 Hz, 1H), 3.06-2.93 (m, 2H), 1.35-1.30 (m, 1H), 1.30 (t, J=7.2 Hz, 1H), 0.81-0.76 (m, 1H), 0.67-0.61 (m, 2H), 0.54-0.49 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1.C(N([CH2:34][CH3:35])CC)C.[C:36]([O-:39])(O)=O.[Na+]>[Cl-]>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1)(=[O:39])[C:35]1[CH:34]=[CH:6][CH:28]=[CH:2][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Product: COC(OC)[C@]1(C)Oc2ccc(NC(=O)c3ccccc3)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Yield: 92 %

Procedure:
80 mg (0.20 mmol) of the compound obtained in Example 17 was dissolved in 1 ml of tetrahydropurane, to which 23 μl (0.20 mmol) of benzoil chloride and 42 μl (0.30 mmol) of triethylamine were added. They were reacted at room temperature for 1 hour. Then, 10 ml of saturated NaHCO3 solution was added and extraction was performed with 30 ml of ethyl acetate. Organic layer was washed with brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 93 mg (yield: 92%) of the target compound.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:8])[C:4]([CH3:7])=[CH:5][N:6]=1.[NH2:9][C:10]1[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=1.Cl[C:18]1[C:19]2[N:27]=[C:26](Cl)[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[CH3:8][N:3]1[C:4]([CH3:7])=[CH:5][N:6]=[C:2]1[S:1][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:9][C:10]3[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=3)[C:19]=2[N:27]=1
Reactant: Cc1cnc(N)cn1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Cc1cnc(S)n1C
Product: Cc1cnc(Nc2ncnc3ccc(Sc4ncc(C)n4C)nc23)cn1

Procedure:
The compound of Example 47 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 2-mercapto-1,5-dimethylimidazole, 2-amino-5-methylpyrazine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:19][N:12]([C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(c1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CN(c1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(N-methylanilino)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 150°-152° C.) and piperazine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(Br)(Br)(Br)[Br:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[Br:49][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCO)c5)c4)cc23)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A suspension of Intermediate 77 (0.65 g, 1.0 mmol) and carbon tetrabromide (1.0 g, 3.0 mmol) in dichloromethane (14 mL) was sonicated for 5 minutes and then cooled in an ice-water bath. Following the addition, via syringe, of a triphenylphosphine (0.52 g, 2.0 mmol) solution in tetrahydrofuran, the cooling bath was removed, allowing the mixture to stir overnight at room temperature. The mixture was quenched with ethanol and concentrated to foam under reduced pressure. The foam was taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The crude material was again taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was taken up a suspension in acetone and filtered. The concentrated filtrate was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as straw-colored foam (0.35 g, 48%). ES/MS calcd. for C36H32BrN4O5S+ 711.1. Found m/z=711.2 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14](=[O:26])[CH:15]([N:17]2[C@H:20]([S:21][C:22](=[O:24])[CH3:23])[CH2:19][C:18]2=[O:25])O)=[CH:10][CH:9]=1)([O-:7])=[O:6]>O1CCOCC1>[N+:5]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14](=[O:26])[CH:15]([N:17]2[C@H:20]([S:21][C:22](=[O:24])[CH3:23])[CH2:19][C:18]2=[O:25])[Cl:3])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)S[C@@H]1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.86 g (~24 mmol) of thionyl chloride in 20 ml of dioxan is added dropwise to a suspension, stirred at room temperature, of 12 g of poly-Hunig base is a solution of 2.83 g (7.59 mmol) of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 100 ml of dioxan. The mixture is stirred for 1.5 hours at room temperature and filtered off from the poly-Hunig base, which is subsequently washed with dioxan. The filtrate is concentrated in vacuo. The 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester obtained is used in the next stage in crude form.
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[C:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)[CH2:19][CH2:18]1)=[O:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.Cl.C(OCC)(=O)C.C(N(CC)CC)C.[C:52](Cl)(=O)[C:53](C)([CH3:55])[CH3:54].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[CH:33]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:23](=[C:20]3[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][CH:9]([NH:8][C:6](=[O:5])[C:53]([CH3:55])([CH3:54])[CH3:52])[C:10]([O:12][CH3:13])=[O:11])[CH2:22][CH2:21]3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
600 mg (1.19 mmol) of methyl 2-[(t-butoxycarbonyl)amino]-4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoate was dissolved in 5 ml of ethyl acetate. 0.5 ml of 4 N hydrochloric acid/ethyl acetate solution was added to the obtained solution, and they were stirred at 0° C. for 3 hours. After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane. 602 mg (5.95 mmol) of triethylamine and 158 mg (1.31 mmol) of pivaloyl chloride were added to the obtained solution, and they were stirred for 10 minutes. Saturated aqueous sodium hydrogencarbonate solution and water were added to the reaction mixture. After extracting with ethyl acetate 3 times followed by the drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane:ethyl acetate=89:11 to 65:35) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH:12]([N:15](CC)C(C)C)(C)C.CN.CN.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:12][NH2:15])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: CN
Solvent: C1CCOC1
Product: NCc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-2-fluoronitrobenzene (1.2 g) in THF (10 ml) is heated in the presence of N,N-diisopropylethylamine (690 μl) and of methylamine (2M in THF, 3 ml) in a microwave reactor (10° C., 20 min). After 20 min, 100 μl of methylamine THF (2M) are added and the resulting mixture is heated at 105° C. for a further 5 minutes. The reaction medium is concentrated and then taken up in ethyl acetate, and washed with water and then with brine. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. (5-Bromo-2-nitrophenyl)methylamine (1.2 g) is isolated in the form of an orange solid which is used as it is in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([O-])=[O:28])[CH3:24].[Na+].Cl.O1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: C=C(CN(C)C)C(=O)[O-]
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C=C(CN(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 8 h

Procedure:
To methyl 2-[(dimethylamino)methyl]prop-2-enoate (314 mg, 2.19 mmol) in tetrahydrofuran (1.4 mL) and water (1.4 mL) was added LiOH (52.5 mg, 2.19 mmol). The solution was stirred at 40° C. for 4 hours, before being frozen and lyophilized to afford sodium 2-[(dimethylamino)methyl]prop-2-enoate which was used as is in the next step as is. To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) in DMF (886 μL) was added sequentially sodium 2-[(dimethylamino)methyl]prop-2-enoate (96 mg, 0.71 mmol), 4 M solution of HCl in dioxane (177 μL, 0.708 mmol), TEA (197 μL, 1.42 mmol), and 1-propanephosphonic acid cyclic anhydride (422 μL, 0.708 mmol) at room temperature. The reaction was stirred overnight before being purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained and the water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-[3-({2-[(dimethylamino)methyl]acryloyl}amino)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H24N5O3 [M+H]+: 394, found 394. 1H NMR (600 MHz, DMSO-D6) δ 12.9 (s, 1H), 11.1 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.77 (d, 1H, J=8.21 Hz), 7.42 (t, 1H, J=8.21 Hz), 7.35 (d, 1H, J=7.63 Hz), 6.01 (s, 1H), 5.58 (s, 1H), 3.87 (q, 2H, J=7.04 Hz), 3.23 (s, 2H), 2.24 (s, 6H), 0.86 (t, 3H, J=7.04 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:21])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reaction time: 0.02 h
Yield: 39.5 %

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (1 eq, 71 mg, 0.27 mmol) in dimethylformamide (0.5 mL) was added potassium carbonate (5 eq, 0.18 g, 0.1.35 mmol). After 1 min, iodomethane (3 eq, 0.05 mL, 0.81 mmol) was added and the suspension was stirred for 2 hours, poured into water (5 mL) and the product was extracted with ethyl acetate (3×5 mL). The layers were then separated, the aqueous layer extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (30 mg, 41%) as a white solid; MS (ES) m/z 280 (M−H)−; Anal. Calcd. For C16H15N3O2: C, 68.3; H, 5.37; N, 14.9. Found, C, 68.4; H, 5.51; N, 14.6.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O.[Cl-].[Na+]>C(O)C>[CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCc2ccccc21
Yield: 88.5 %

Procedure:
1.28 g of 1-indanone in 13 ml of anhydrous ethanol is cooled to +5° C. 0.23 g of sodium borohydride at 95% is added in small fractions, with agitation at +10° C. for one hour. 0.23 g of sodium borohydride at 95% is again added at +5° C., with agitation at 20° C. for one hour 30 minutes. The reaction mixture is poured into 60 ml of water containing sodium chloride and is extracted with isopropyl ether; the extracts are dried and brought to dryness under reduced pressure and the residue is chromatographed on silica in a hexane-ethyl acetate mixture (6-4). 1.15 g of expected product is isolated.
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N:19]([O-])=[O:20].[Na+]>O.C(O)(=O)C>[C@@H:1]1([NH:12][C:13]([N:15]([N:19]=[O:20])[CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.1 %

Procedure:
1-(β-D-glucopyranosyl)-3-n-propylurea (1.50 g) was dissolved in a mixture of water (10 ml) and acetic acid (2 ml), and to the resulting solution was added 560 mg (1.5 mol. equivalents) of sodium nitrite at ambient temperature under stirring to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) for the removal of sodium ion and then concentrated to dryness below 35° C. and under a reduced pressure. Crystallisation of the residue from n-propanol gave 1.35 g of the titled compound. Yield 80%. mp. 112° C. (decomposition with foaming). [α]D21 -6° (c 1.0, H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32]>>[C:31]([NH:30][CH2:29][CH2:28][NH:27][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:22])(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 39 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.056 mmol) described in example 92 and N-(2-aminoethyl)acetamide (74 mg, 0.730 mmol), was prepared N-[2-(acetylamino)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (9 mg, 39% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.39 (br s, 1 H), 8.56 (s, 1 H), 7.39 (s, 1 H), 7.17-7.15 (m, 2 H), 7.04-6.94 (m, 2 H), 6.09 (br s, 1 H), 4.13 (s, 2 H), 3.61-3.58 (m, 2 H), 3.57 (s, 3 H), 3.51-3.48 (m, 2 H), 1.98 (s, 3 H); MS m/z 413 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].O.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[C:12]#[N:13]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(CO)cc1F
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-3-fluorobenzyl alcohol, as described in Step B above, (20 g, 0.097 mol) was dissolved in DMF (100 mL) then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh2)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95° C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5).