Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][N:3]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.0 grams (0.015 mole) of 2-amino-3-cyano-5-bromopyrazine and 2.1 grams (0.021 mole) of trimethylsilylacetylene in 50 mL of acetonitrile is stirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. The reaction mixture is warmed to 70° C., where it is stirred for about 7.5 hours. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous, dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using tetrahydrofuran/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-(trimethylsilylethynyl)pyrazine.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH2:16][CH:17]4[CH2:19][CH2:18]4)[N:14]=[N:15][C:11]=3[C:10]=2[Cl:22])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30].O>O1CCCC1>[Cl:22][C:10]1[C:11]2[N:15]=[N:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:12]=2[CH:20]=[CH:21][C:9]=1[O:8][C:3]1[C:2]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)=O
Reactant: Clc1c(Oc2ncccc2Br)ccc2c1nnn2CC1CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
5-[(3-Bromopyridin-2-yl)oxy]-4-chloro-1-(cyclopropylmethyl)-1H-benzotriazole (395, 33 mg, 0.09 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (2 mL), cooled to −70° C. and treated dropwise with n-butyllithium (2.5 M in tetrahydrofuran, 0.038 mL, 0.10 mmol, 1.1 equiv.). After 5 minutes, the mixture was treated with acetone (7.57 mg, 0.13 mmol, 1.5 equiv.). After an additional ten minutes at −70° C., the mixture was treated with water. The mixture was poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC (80:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (saturated aqueous, 20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound 396 as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.10 (dd, 1H, J=7.6, 1.9 Hz), 7.97 (d, 1H, J=8.9 Hz), 7.88 (dd, 1H, J=4.8, 1.8 Hz), 7.44 (d, 1H, J=9.2 Hz), 7.14 (dd, 1H, J=7.4, 4.6 Hz), 4.66 (d, 2H, J=7.5 Hz), 1.68 (s, 6H), 1.45-1.38 (m, 1H), 0.60-0.57 (m, 2H), 0.52-0.49 (m, 2H) ppm. High resolution mass spectrometry (ES+) m/z 359.1277 [(M+H)+; calculated for C18H20ClN4O2: 359.1269].
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>CS(C)=O.O>[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
To a solution of (3-carboxypropy)triphenylphosphonium bromide (25 g, 58.3 mmol) in DMSO (53 mL) was added t-BuOK (12.4 g, 110.7 mmol). The mixture was stirred at rt for 20 min. Then a solution of 3-Bromo-benzaldehyde (9.3 g, 50.3 mmol) in DMSO (15 mL) was added dropwise. The reaction mixture was stirred at rt for 4 h. The mixture was poured in water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography using a solvent system of 5:1 petroleum ether/EtOAc to give 5-(3-Bromo-phenyl)-pent-4-enoic acid (4.8 g, 38%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.45 (s, 1H), 7.2-7.25 (m, 1H), 7.1-7.15 (m, 2H), 6.4-6.45 (m, 1H), 6.23-6.3 (m, 1H), 2.4-2.6 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.CN(C)[CH:49]=[O:50]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:49]([C:33]2[CH:32]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]([CH3:23])[CH3:34])=[O:50])=[CH:20][CH:21]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CN(C)C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccccc4N(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) and commercially available 4-(dimethylamino)benzoic acid (44 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (83 mg) was added, and the admixture was stirred at room temperature for 16 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 7 mg of the title compound (yield: 10%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH:6]=1)=O.[CH2:23]([Mg]Br)[CH3:24].[CH2:27]1COC[CH2:28]1>>[CH2:16]([O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([OH:2])([CH2:23][CH3:24])[CH2:27][CH3:28])[CH:14]=[CH:13]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: CCC(O)(CC)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Cool 6-benzyloxynaphthalene-2-carboxylic acid methyl ester (5.75 g, 19.67 mmol) in THF (115 mL) to about 0° C. and treat the solution dropwise with ethyl magnesium bromide (23.0 mL, 69.0 mmol, 3.0 M in ether). Allow the reaction to warm to RT and stir it for 3 h. Quench with water and concentrate. Dissolve the crude residue in CH2CL2 (200 mL), wash twice with brine, dry over Na2SO4 and filter. Concentrate the filtrate to give the title compound as a yellow solid (6.0 g, 95%). MS (ES) m/e 321 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[C@H:11]([NH2:22])[CH2:10][C@@H:9]1[CH:23]1[CH2:25][CH2:24]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH:31]=O.Cl[C:43]([O:45][CH3:46])=[O:44]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:19])([F:21])[F:20])=[CH:15][CH:16]=2)[C@H:11]([N:22]([CH2:31][C:30]2[CH:29]=[C:28]([C:27]([F:41])([F:40])[F:26])[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=2)[C:43]([O:45][CH3:46])=[O:44])[CH2:10][C@@H:9]1[CH:23]1[CH2:24][CH2:25]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N)C[C@@H]1C1CC1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21

Procedure:
cis-4-Amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (Example 107C) (1.0 g) was subjected to reductive amination (with 3,5-bis(trifluoromethyl)benzaldehyde as in Example 4 and acylation with methyl chloroformate as in Example 5) to afford 2.4 g of the title compound. MS m/z 640 (M+); 1H NMR (CDCl3) δ 1.5 (s, 9H), 3.8 (s, 3H), 7.1 (s, 1H), 7.5-8.0 (m, 4H).
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[NH:9][C:10]1[C:11]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[NH:16][C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[BrH:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[NH:9][C:10]1[C:11]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Oc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
With the exclusion of moisture, at approximately 0° C., 6 ml of boron tribromide in 100 ml of methylene chloride are added within the course of 40 min to 2.0 g (5.7 mmol) of 4-(3-chloro-anilino)-6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine in 60 ml of methylene chloride. After 21 hours' stirring at RT the reaction mixture is filtered. The crude product is precipitated from the filtrate with approximately 1 liter of hexane, filtered off and washed with hexane. The residue is taken up in 0.2 liter of water and 0.6 liter of ethyl acetate and rendered neutral with 5% NaHCO3 solution. The organic phase is separated off, washed with water and brine, dried over MgSO4 and concentrated by evaporation. Crystallization from hot methanol with hexane yields the title compound; analysis calculated for C18H14N4OBrCl (+0.13 H2O): C 51.47%, H 3.36%, N 13.34%, Br 19.02%, Cl 8.44%; found: C 51.58%, H 3.32%, N 13.37%, Br 19.29%, Cl 8.46%; 1H-NMR (360 MHz, DMSO-d6): 12.85 and 10.60 (2sb, 2H), 10.5-9.5 (sb), 8.37 (s, 1H), 7.92 (s, 1H), 7.67 (d, J=8, 2H), 7.63 (d, J=8, 1H), 7.51 (dd, J=8, 1 H), 7.33 (d, J=8, 1H), 7.06 (s, 1H), 6.90 (d, J=8, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:24])[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:28](OC)([N:30](C)C)[CH3:29].[NH2:35]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:24])[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:35][NH:30][C:28]([CH3:29])=[C:10]2[N:9]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Reactant: COCCOc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Product: COCCOc1cc2c(cc1F)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVf) was prepared by reacting 0.0026 moles of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-thione (IIf) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[Cl:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([O:43]CC)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([OH:43])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:47][CH:48]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(Cl)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Yield: 96 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 96% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.2 Hz, 2H), 4.39 (s, 2H), 4.06-3.91 (m, 2H), 3.51-3.39 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 352.2 (M+1), 354.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C@:8]2([CH3:14])[CH2:12][O:11]C(=O)[NH:9]2)[CH:7]=1.C(O)C.O.[OH-].[Li+]>O>[NH2:9][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:15])([CH3:14])[CH2:12][OH:11]
Reactant: C[C@@]1(c2cc(Br)ccc2F)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of the (R)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one (8.94 g, 33 mmol) in a 1:1-mixture of ethanol and water (120 ml) was treated with lithium hydroxide monohydrate (6.85 g, 163 mmol) and the reaction mixture was stirred at 100° C. overnight. For the workup, the reaction mixture was evaporated at reduced pressure and the residue dissolved in ethyl acetate (90 ml), then extracted with hydrochloric acid (2N, 90 ml). The aqueous layer was treated with a solution of sodium hydroxide (2N, 100 ml) and solid sodium chloride was added until saturation. The following extraction with ethyl acetate (3×200 ml) and the evaporation of the combined organic layers after drying over sodium sulphate yielded the (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol as a white crystalline solid (7.90 g, 98% of theory, e.e.>98%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[CH3:11]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(F)c1C

Procedure:
3-Fluoro-2-methyl-benzoic acid (4.8 g, 31 mmol), potassium carbonate (4.3 g, 31 mmol) and methyl iodide (4.5 g, 31 mmol) were stirred at room temperature for 17.5 hours in anhydrous N,N-dimethylformamide (50 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic, layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 4.8 g (27 mmol, 87% in yield) of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Cn2cncn2)cc1

Procedure:
A mixture of 34.2 parts by weight of benzyl bromide, 13.8 parts by weight of 1,2,4-triazole and 41.4 parts by weight of potassium carbonate in 150 parts by weight of acetonitrile is refluxed for 10 hours while stirring. The mixture is filtered and the filtrate is evaporated to dryness and recrystallized from a mixture of toluene and cyclohexane. There is obtained 21 parts by weight of 1-benzyl-1,2,4-triazole; m.p.: 58° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Clc1cccc(CBr)c1
Reactant: N#Cc1ccc(NC2CCNCC2)nn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(Cc3cccc(Cl)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 39.2 %

Procedure:
A mixture of 6-(piperidin-4-ylamino)-pyridazine-3-carbonitrile (D3) (0.150 g, 0.74 mmol), 3-chlorobenzyl bromide (0.102 ml, 0.78 mol) and diisopropylethylamine (0.196 ml, 1.11 mol) in acetonitrile (2 ml) was stirred at 120° C. for 5 min., under microwave irradiation (Biotage MW-oven). The reaction mixture was then diluted with dichloromethane and extracted with a saturated solution of sodium carbonate. The organic layers were separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; 0-2.5% ammonia in methanol (7 M)/dichloromethane). The desired fractions were collected and evaporated in vacuo, and the residue triturated with diisopropylether to yield E13 (0.095 g, 39%) as a white solid. C17H18ClN5 requires 327. Found 328 (MH+); mp: 151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])=[C:5]2[OH:24].[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]([CH3:25])[CH:7]=[C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])[C:5]2=[O:24]
Reactant: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1nc2c(cc1Br)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 6-bromo-N-(4-chlorobenzyl)4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxamide (0.400 g, 0.98 mmol) and potassium carbonate (0.54 g, 3.92 mmol) in 5 mL DMF at room temperature is added dropwise methyl iodide (0.167 g, 1.18 mmol). The mixture is stirred at room temperature for 30 min then diluted with water. The resulting solid is filtered, washed with water and dried. The crude product is triturated with EtOAc/hexanes to yield 0.358 g (85%) of the desired product as a white solid. Physical characteristics are as follows: m.p. 266-268° C.; 1H NMR (CDCl3) δ10.18, 8.92, 8.83, 7.30, 4.65, 4.03, 2.82; Anal. Calcd for C18H15BrClN3O2: C, 51.39; H, 3.59; N, 9.99; Found: C, 51.02; H, 3.57; N, 9.94.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][Mg]Cl.Cl[Si:13]([CH2:16][Cl:17])([CH3:15])[CH3:14]>>[Cl:17][CH2:16][Si:13]([CH2:4][C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:15])[CH3:14]
Reactant: C[Si](C)(Cl)CCl
Reactant: Fc1ccc(C[Mg]Cl)c(F)c1
Product: C[Si](C)(CCl)Cc1ccc(F)cc1F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield from 2,4-difluorobenzylmagnesium chloride and chlorochloromethyldimethylsilane by the method described in Example 5, Step A.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Yield: 65.2 %

Procedure:
The same procedures as in Example 140 were carried out from the compound obtained in Example 139 (6.2 g), potassium carbonate (3.6 g), iodomethane (1.6 mL), and DMF (100 mL), to give the captioned compound (4.2 g, 65%) as an oily product.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[S:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+]>CC(N(C)C)=O>[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[C:10](=[O:17])[C:9]3[CH2:19][CH2:18][S:20][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)SCC2
Temperature: 0 °C

Procedure:
A solution of 3,5-dihydro-5-phenyl-furo-[3,2-c][1,8]naphthyridin-4(2H)-thione (500 mg.) and sodium iodide (500 mg.) in dry dimethylacetamide (5 ml.) was stirred in an atmosphere of nitrogen and heated at 125° for 2 hr. After cooling, the solution was poured into ice-water, filtered, washed with water and dried to yield the desired product, m.p. 260°-261° C.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11]Cl)[N:10]=1)[C:3]([NH2:5])=[NH:4].[SH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[OH-].[Na+]>CCO.O>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(CCl)cs1
Reactant: COC(=O)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)CCSCc1csc(NC(=N)N)n1
Reaction time: 18 h

Procedure:
To 2-guanidino-4-chloromethylthiazole hydrochloride (3.86 g.) and methyl 3-mercaptopropionate (3.0 g.) in EtOH (45 ml.) at 0° was added sodium hydroxide (1.6 g.) in water (15 ml.) over 15 minutes. The reaction mixture was allowed to attain room temperature and to stand for 18 hours. The solution was poured into water and extracted with EtOAc. The extract was washed with aqueous sodium hydroxide solution, water, dried and evaporated to give methyl 3-(2-guanidinothiazol-4-yl-methylthio)propionate as a yellow oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[C:1]([O:5][C:6](=[O:19])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[N:15]=1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (98 g) synthesized in Example 4 and triethylamine (50 mL) were dissolved in dichloromethane (800 mL), methanesulfonyl chloride (38.8 g) was added dropwise under ice-cooling, and the mixture was stirred for 2 hr at 0° C. Water was added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The title compound was quantitatively obtained as a crude brown oil and used as it was for the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:18].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([F:18])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-proline, 24d, (215.3 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 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 170.3 mg of 25d as a colorless oil. FTIR (neat) 1850 cm−1.