Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[NH2:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22]>C(O)C>[C:1]([NH:3][CH:4]=[N:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])#[N:2]
Reactant: CCOC=NC#N
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1N
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=CNC#N
Temperature: 25 °C
Reaction time: 45 h
Yield: 35.5 %

Procedure:
Ethyl N-cyanoformimidate (3.2 g) was added to a suspension of 3-amino-7-chloro-2-methylimidazo[2,1-a]isoquinoline (2.3 g) in ethanol (60 ml) and the mixture was stirred at room temperature for 45 hours. The mixture was evaporated in vacuo and the residual solid was washed successively with diethyl ether and ethyl acetate to give N-cyano-N'-(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)formamidine (1.0 g).
Reaction SMILES: C(OC([N:6]=[S@:7]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C@@H:26]([CH2:29][OH:30])[CH2:27][CH3:28])[C:22]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][N:20]=2)=[CH:14][CH:13]=1)([CH:9]1[CH2:11][CH2:10]1)=[O:8])=O)C.CC[O-].[Na+]>>[OH:30][CH2:29][C@H:26]([NH:25][C:23]1[C:22]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[CH:21][N:20]=[C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([S@:7]([CH:9]3[CH2:11][CH2:10]3)(=[NH:6])=[O:8])=[CH:17][CH:16]=2)[N:24]=1)[CH2:27][CH3:28]
Reactant: CCOC(=O)N=[S@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Agent: CC[O-]
Agent: [Na+]
Product: CC[C@H](CO)Nc1nc(Nc2ccc([S@](=N)(=O)C3CC3)cc2)ncc1-c1cccs1
Yield: 81 %

Procedure:
In the reaction of (R)—N-(ethoxycarbonyl)-S-(4-{[4-{[(R)-1-(hydroxymethyl)propyl]-amino}-5-(2-thienyl)pyrimidine-2-yl]amino}phenyl)-S-cyclopropylsulfoximide with sodium ethylate according to procedure 14, the desired product is obtained in 81% yield after chromatographic purification (silica gel, dichloromethane/ethanol (0-10% ethanol)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 0 °C

Procedure:
4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at −50° C. During the adding of the mixture, the temperature was held at −50° C. and then allowed to warm to 0° C. within 3 h.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([CH2:14][N:15]2[N:43]=[C:19]3[CH2:20][C:21](=O)[C:22]4[CH2:23][S:24][N:25]=[C:26]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:17]([C:18]=43)=[N:16]2)[C:8]=1[CH3:44].O1CCCC1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]([NH:4][CH:21]1[C:22]2[CH2:23][S:24][N:25]=[C:26]([NH2:27])[C:17]3=[N:16][N:15]([CH2:14][C:9]4[C:8]([CH3:44])=[C:7]([O:6][CH3:5])[C:12]([CH3:13])=[CH:11][N:10]=4)[N:43]=[C:19]([C:18]=23)[CH2:20]1)([CH3:3])[CH3:2]
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1c(C)cnc(CN2N=C3CC(NC(C)C)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Isopropylamine (5.5 μl) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (30 mg), methanol (0.4 ml), tetrahydrofuran (0.2 ml) and acetic acid (12 μl), and then the mixture was stirred at room temperature for two hours. A solution of sodium cyanoborohydride (10 mg) in methanol (0.4 ml) was added to the reaction mixture, followed by stirring at room temperature overnight. The reaction mixture was concentrated, and a 0.2 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (1 ml) and trifluoroacetic acid (0.25 ml) were added to the resulting residue, and the mixture was stirred at room temperature for five hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (chloroform-methanol). The resulting oil was dissolved in dioxane, followed by lyophilization to obtain the title compound (6.3 mg, 29%) as an amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].Cl[C:20]1[S:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:20]3[S:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: CC(C)c1nsc(Cl)n1
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)NCc1cc(-c2ccn(-c3nc(C(C)C)ns3)n2)ccc1Cl
Temperature: 165 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Step B, Example 4) (0.02 g, 0.75 mmol), 5-chloro-3-(1-methylethyl)-1,2,4-thiadiazole (i.e. the product of Step A) (0.61 g, 3.75 mmol) and potassium carbonate (0.25 g, 1.5 mmol) in N-methyl-2-pyrrolidinone (2.5 mL) was heated in a Biotage Creator XM microwave apparatus at 165° C. for 15 minutes. The reaction mixture was poured into water (60 mL), and the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.5 g).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3cc(F)cc(F)c3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1cc(F)cc(F)c1

Procedure:
The 2-trifluoroacetamido-3-(3,5-difluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (10.2 g, 22.9 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 4.93 g. (61.6%). EA, MS(FD).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/C[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC[C@@H](C)NC(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
A suspension of (R,E)-ethyl 5-(tert-butoxycarbonylamino)hex-2-enoate (1.70 g, 6.61 mmol) and 5% Pd/C (350 mg) in ethanol (35 mL) was vigorously stirred under the atmosphere of hydrogen balloon for 1.5 hr. The reaction mixture was filtered and the filtrate were concentrated to give (R)-ethyl 5-(tert-butoxycarbonylamino)hexanoate (1.71 g, 6.58 mmol, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.34 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.66 (s, 1H), 2.31 (td, J=7.5, 1.6 Hz, 2H), 1.75-1.57 (m, 2H), 1.51-1.38 (m, 2H), 1.44 (s, 9H), 1.25 (t, J=7.1 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5](=[O:7])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:20]=2)([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:3]=1.[OH-].[K+].Cl[CH:35]([F:37])[F:36]>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH:35]([F:37])[F:36])[C:5](=[O:7])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[CH:31]=[N:30][CH:29]=[N:28][CH:27]=3)[CH:20]=2)([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:17])([F:16])[F:18])=[CH:12][CH:13]=2)[N:3]=1
Reactant: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(-c3cncnc3)c2)C(=O)N1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(-c3cncnc3)c2)C(=O)N1C(F)F
Temperature: -45 °C
Yield: 14 %

Procedure:
A solution of 2-amino-5-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one (0.398 g, 0.92 mmol) in dimethylformamide is treated with KOH (0.057 g, 1.01 mmol), cooled to −45° C., and bubbled with chlorodifluoromethane (1.40 g, 17.6 mmol). The reaction vessel is sealed and heated at 70° C. for 18 h. The reaction is cooled to room temperature, quenched by careful addition to water, extracted with ethyl acetate, diluted with brine and extracted again with ethyl acetate. The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The resultant residue is purified twice by flash chromatography (silica, 95:5:0.5 to 90:10:0.5 methylene chloride/methanol/concentrated ammonium hydroxide and 100:0 to 98:2 methylene chloride/methanol as eluents) to afford the title compound as a white solid, 0.064 g (14% yield), mp 82-94° C., identified by HNMR, infrared and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 8.89 (s, 2H), 7.64-7.60 (m, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.23-7.18 (m, 3H), 6.95 (t, J=58 Hz, 1H), 4.92 (br s, 2H); IR (ATR) 3497, 3309, 3149, 1761, 1678, 1497, 1449, 1416, 1252, 1212, 1162 cm−1; ESI MS m/z 482 [C21H13F6N5O2+H]+;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:18]([I:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[I:24][C:18]1[C:17]([O:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(I)n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (229 mg), 3-hydroxy-2-iodo-6-methylpyridine (486 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give the title compound (47 mg, yield 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28]C)=[N:13][C:14]=1[CH2:15]C.ClC1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C.CI>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH3:15]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CI
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and methyl iodide, and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.51, 7.43, 7.37-7.25, 5.86, 5.40, 4.28, 3.43, 3.23, 3.06, 2.42, 2.25; HRMS (FAB) calcd for C22H21Cl2N3O+H 414.1140, found 414.1143.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)N1C(=O)CC[C@H]1C(=O)O
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
1-(1-Methylethyl)-5-oxo-proline (0.060 g, 0.35 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.052 g, 0.39 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.061 g, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.074 g, 0.39 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-(1-methylethyl)-5-oxo-prolinamide (0.032 g) as a white solid. LC/MS [M+H]+=313.1, retention time=2.26 minutes.
Reaction SMILES: S(O[CH2:6][CH2:7][CH:8]=[C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)(C)(=O)=O.OC1C=CC(CC(OCC)C(OCC)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH:8](=[C:9]1[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2)[CH:7]=[CH2:6]
Reactant: CS(=O)(=O)OCCC=C1c2ccccc2CCc2ccccc21
Agent: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CC=C1c2ccccc2CCc2ccccc21
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of 5-(3-mesyloxypropylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (5.0 g, 15.2 mmol), ethyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (3.7 g, 15.5 mmol), potassium carbonate (2.9 g, 21 mmol) and dimethylformamide (10 ml) was heated at 100° C. for 5 h. Benzene (200 ml) and water (200 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with benzene/chloroform, to give first 2.5 g of 5-propenylidene-10,11-dihydro-5H-dibenzo(a,d)cyclohepten and then 1.5 g (21%) of the title compound as an oil. 1H NMR (250 MHz, CDCl3) δ7.10-7.35 (m, 10 H); 6.85 (d, 2 H); 6.06 (t, 1 H); 4.27 (q, 2 H); 4.07 (m, 3 H); 3.68 (m, 1 H); 3.45 (m, 1 H); 3.17 (bs, 4 H); 3.06 (d, 2 H); 2.69 (q, 2 H); 1.27 (t, 3 H); 0.99 (t, 3 H).
Reaction SMILES: [H-].[Na+].CO.[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[CH:21]N(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(F)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To an oven-dried round bottom flask was added 1.87 g of a 60% oil dispersion of NaH (46.8 mmol), DMF (50 mL), and methanol (1.89 mL; 46.8 mmol) under a N2 atmosphere. To this suspension was added a solution of 2-cyanoacetamide (1.97 g; 23.4 mmol) in DMF (10 mL) via syringe followed by a solution of the crude product of Step B (21.3 mmol) in DMF (20 mL). The resulting reaction mixture was heated to 95° C. and stirred for 3 hours. The reaction was the quenched with saturated aqueous NaHSO4 solution and extracted with methylene chloride (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by trituration in ethanol. The precipitate was collected and washed with cold ethanol to afford the desired product: m/e=359 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].O>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Yield: 91.9 %

Procedure:
Under a dry argon atmosphere, a borane-tetrahydrofuran complex (39.7 g, 0.463 mole) as a 1 M solution in tetrahydrofuran was added slowly to a stirred solution of 2,6-dimethyl-3-nitrobenzoic acid (60.2 g, 0.308 mole) in 350 ml of anhydrous tetrahydrofuran. The reaction mixture was heated at 60° for approximately 18 hours. Water (20 ml) was slowly added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure to give a residue. The residue was washed with three 100 ml portions of methylene chloride, then three 100 ml portions of a 2 N aqueous sodium hydroxide. The washes were combined and the organic phase separated. The aqueous phase was washed with four 250 ml portions of methylene chloride, and the organic phases were combined, dried with anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give 2,6-dimethyl-3-nitrobenzene-1-methanol (51.3 g, mp 86.5°-88.5°).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][S:3]1.C1C=CC=CC=1.[Br:14][CH:15]([Br:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>O>[CH3:1][C:2]1([CH3:7])[N:6]([C:16](=[O:17])[CH:15]([Br:19])[Br:14])[CH2:5][CH2:4][S:3]1
Reactant: CC1(C)NCCS1
Reactant: O=C(Cl)C(Br)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1(C)SCCN1C(=O)C(Br)Br

Procedure:
To a mixture of 3.5 g. of 2,2-dimethyl thiazolidine, 50 ml. of benzene and 7.1 g. of dibromoacetyl chloride mixed in an ice bath was added 3.1 g. of triethylamine dropwise with stirring and continued cooling. When reaction was complete, the mixture was poured into water and the benzene layer separated, dried over magnesium sulfate and the benzene removed under vacuum. Yield was 8.5 g. of a dark oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[S:39][C:38]([CH:40]=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[S:39][C:38]([C:40]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(N2CCC(O)CC2)s1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCC(O)CC4)s3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 417 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 5-(4-hydroxypiperidinyl)thiophene-2-carboxaldehyde. [M+H]+ calcd for C27H29N5O3S: 504.20; found: 503.99.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]=[N+]=[N-])[C:9]=2[CH:8]=[N:7]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N
Yield: 98.5 %

Procedure:
A solution of ((R)-4-azido-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (1.25 g, 5.0 mmol) in ethanol (40 mL) was hydrogenated over 10% Pd/C (130 mg) under 30 psi in a 150 mL Parr bottle at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite® (diatomite filter). The filtrate was collected and concentrated in vacuo to afford ((R)-4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester as an oil (1.10 g, 98%), which was used in the next step without further purification. MS calcd. for C11H17N3O2 223, obsd. (ESI+) [(M+H)+] 224.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[NH:11][C:10](=O)[C@H:9]([CH3:14])[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCOCC1>[CH3:14][C@@H:9]1[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[C:12]=2[NH:11][CH2:10]1
Reactant: C[C@@H]1NC(=O)c2cccc(N)c2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CNc2c(N)cccc2CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
14.8 g (0.072 mol) of (S)-9-amino-3-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione in 455 ml of dioxane are heated at the reflux temperature with stirring for 48 hours in the presence of 17 g of lithium aluminium hydride. The reaction mixture is cooled in an ice bath and then, slowly and successively, 17 ml of water, 17 ml of a 5N sodium hydroxide solution and 45 ml of water are added. The mixture is left stirring for 2 hours at room temperature, filtration is carried out and washing is carried out with hot tetrahydrofuran and with dichloromethane. The organic phase is recovered and is concentrated. There are obtained 12.7 g of product which is used as is in the following stage.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:24])[C:5]1=[O:35].C(N(C(C)C)CC)(C)C.[CH3:45][N:46]([CH:48]=[O:49])[CH3:47]>>[CH3:45][N:46]([CH3:47])[C:48]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:24])[C:5]1=[O:35])=[O:49]
Reactant: CN(C)C=O
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(4-morpholinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0055 mL, 0.06 mmol)@40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue treated with 1N NaHSO4. Extracted the mixture 3× with EtOAc and concentrated the organics. The residue was then dissolved in EtOAc and washed with saturated NaHCO3 (aqueous) then concentrated the organics. Triturated the residue with Et2O, filtered, and dried in vacuo to provide the title compound as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66-1.79 (m, 2 H), 1.76-1.93 (m, 1 H), 2.35 (t, J=6.18 Hz, 6 H), 2.70 (s, 6 H), 3.19-3.31 (m, 2 H), 3.40-3.48 (m, 2 H), 3.53-3.63 (m, 4 H), 4.11 (s, 2 H), 4.25 (s, 2 H), 6.54-6.59 (m, 1 H), 7.14 (t, J=8.84 Hz, 2 H), 7.37-7.44 (m, 2 H), 8.17-8.39 (m, 1 H), 8.52 (s, 1 H), 10.38 (s, 1 H); ES+ MS: 555 (M+H+).