Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.B1([C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2cncnc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 5.6 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (71 mg, 0.22 mmol), pyrimidyl-5-boronic acid pinacolate (89 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mMol) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate, followed by trituration with ethyl acetate afforded 4 mg (6%) of 3-(2-pyridyl)-5-(3-cyano-5-(5-pyrimidyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ−9.37 (s, 1H), 9.07 (s, 2H), 8.89 (d, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.26 (d, 1H), 8.11 (s, 1H), 7.94 (t, 1H), 7.52 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(C2(Oc3cnccn3)CCNCC2)cc1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
A mixture of 4-phenyl-4-piperidinol (7.1 g, 40 mM), DMSO (50 ml) and sodium hydride (2 g of a 50% dispersion in oil) was heated at 80° until homogenous, cooled to room temperature and treated with chloropyrazine (4.6 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured on to water (250 ml) and extracted with toluene (2×250 ml). The combined organic phases were washed with brine, dried and the solvents removed under reduced pressure. Sublimation of the residue at 0.1 mm Hg (bath temp. 100°) gave the title compound (400 mg) m.p. 107°-8°.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[O:5]CC1C=CC(Cl)=CC=1Cl>C(Cl)Cl>[CH3:1][O:2][CH:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[OH:5]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 3 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in 1.8 L of methylene chloride that was cooled to 0° C., was added dropwise a solution of stannous chloride (31.522 mL, 0.2676 mol) in 134 mL of methylene chloride while stirring. After maintaining the solution at about 3° C. for approximately 27 hours, another 5.031 mL of stannous chloride (SnCl4) (0.04282 mol) was added and the solution was kept at about 3° C. overnight. After a total reaction time of approximately 43 hours, the reaction was quenched by carefully adding the solution to 1.9 L of a saturated NaHCO3 solution. Tin salts were removed via filtration through Celite after which the organic phase was isolated, dried with MgSO4 and evaporated in vacuo. The yield of raw, dark yellow oil was 173.6 g. The crude oil was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:11]([Mg]Br)([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([OH:5])[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a solution of 2-bromobenzoyl chloride (1.3 mL, 9.9 mmol) in dry tetrahydrofuran (38 mL) at 0° C. under nitrogen was added dropwise a 2.0 M solution of isopropylmagnesium bromide in tetrahydrofuran (12.4 mL, 24.8 mmol) over ca. 5 minutes. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 27 hours. The reaction was quenched by the addition of 1 M aqueous hydrochloric acid (30 mL) and concentrated in vacuo to remove tetrahydrofuran. The aqueous phase was diluted to ca. 50 mL with water and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as an orange oil (2.1 g). Purification by flash chromatography using a solvent gradient of 1 to 4% ethyl acetate in hexane gave the title compound (0.77 g, 33%) as a clear, pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C[O:32][CH2:31][CH2:30]1.CC(O)=O.B(F)(F)F>CCOCC.C(O)CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]3([CH3:2])[O:32][CH2:31][CH2:30][O:3]3)=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[C:15]([C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[O:28])[CH:16]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: OCCO
Solvent: CC(=O)O
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)OCCO1

Procedure:
A solution consisting of 0.21 g of 4-acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide, 2 mL anhydrous THF, 50 μL AcOH and 400 μL ethylene glycol was prepared in a vial. The vial was heated by swaying gently in front of a heat gun, cooled for one minute and 400 μL 46.5% BF3:Et2O were immediately added. The vial was quickly shaken, left standing and an LC-MS sample was taken after 1 minute of reaction. After another minute the reaction mixture was partitioned between 10 mL DCM and 10 mL H2O. To the reaction mixture was then added an additional 20 mL DCM and 20 mL aqueous 1 M NaOH. The pH of the aqueous layer was brought to 3 using HCl and then quickly brought to pH 8-9 using saturated NaHCO3. The DCM layer was collected, the aqueous layer was extracted with DCM (2×20 mL) and all organic layers were combined and concentrated by rotary evaporation. The product was isolated by preparative HPLC, and the fractions containing the product were concentrated to a volume of 15 mL. To this solution was added 3 mL 3 M NaOH and 0.52 g KMnO4. The reaction was stirred at RT, monitored by LC-MS and additional KMnO4 (0.55 g×2) was added at intervals of ca. 2 hours. After a total rxn time of ca. 5 h, the crude mixture was brought to pH 4 using 10% AcOH, extracted with DCM (125 mL) and washed with saturated aqueous NaHCO3. The DCM was removed by rotary evaporation and the product was obtained by preparative HPLC. MS: m/z 459 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])[CH:7]=[N:6][CH:5]=1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:9][N:8]2[C:4]([CH2:3][CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:5][N:6]=[CH:7]2)=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(Cn2cncc2CCO)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cncn1Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The crude residue, 4-[5-(2-hydroxyethyl)imidazol-1-ylmethyl]-3-nitrobenzonitrile, is then taken up in CH2Cl2 (10 mL), cooled to 0° C., and treated with Et3N (0.58 mL, 4.19 mmol). To this solution is added methanesulfonyl chloride (0.13 mL, 1.68 mmol). After 0.5 h the solution is diluted with CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is further extracted with CH2Cl2 (3×20 mL) and the combined layers are dried (Na2SO4) and concentrated to give crude methanesulfonic acid 2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]ethyl ester. A suspension of the methanesulfonic acid 2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]-ethyl ester residue, DMF (17 mL), sodium iodide (0.630 g, 4.19 mmol), Et3N (0.58 mL, 4.19 mmol), and potassium carbonate (0.580 g, 4.19 mmol) is heated to 60° C. for 1 hour and then 75° C. for an additional 2 h. At that point the suspension is concentrated and diluted with CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is further extracted with CH2Cl2 (3×20 mL) and the combined layers are dried (Na2SO4). The residue is then purified via HPLC (reversed phase, CH3CN/H2O) to give 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile as a solid. MS (ESI) m/z 254.9 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.48-2.57 (m, 1 H), 2.81-2.92 (m, 1 H), 2.92-3.01 (m, 1 H), 3.35-3.47 (m, 1 H), 6.03 (dd, J=8.6, 3.5 Hz, 1 H), 6.80 (d, J=8.3 Hz, 1 H), 6.89 (s, 1 H), 7.36 (s, 1 H), 7.81 (dd, J=7.8, 1.8 Hz, 1 H), 8.41 (d, J=1.8 Hz, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:6]1(=[O:24])=[O:23].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.Cl>>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:6](=[O:24])(=[O:23])[N:5]([CH2:4][CH2:3][CH2:2][NH:28][CH:25]3[CH2:27][CH2:26]3)[CH2:10][C:9]=2[CH:11]=1
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Agent: Cl
Product: O=S1(=O)N(CCCNC2CC2)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 96 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(3-bromopropyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{3-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propyl}cyclopropanamine (0.102 g, 96%) as a white solid:
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:10]2[CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:19][CH2:18]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 85 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.35 g (0.79 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.188 g, 0.79 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.38 (9H, s), 1.52 (4H, m), 1.75 (2H, m), 1.90 (2H, m), 2.28 (2H, m), 2.82 (1H, m), 2.92 (2H, m), 3.74 (1H, brs), 3.68 (1H, m), 6.79 (1H, brs), 7.18 (1H, t), 7.26 (4H, d), 7.52 (2H, s), 7.88 (4H, d), 8.38 (1H, d).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:14][CH2:15][C:16]([N:11]1[CH2:10][CH2:9][CH:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CCN(C(=O)CCl)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of N-(1,1-dimethylethyl)-4-piperidinecarboxamide (201 g, 1.0 mol) in dichloromethane (1 L) was cooled under nitrogen to −5° C., and chloroacetyl chloride (124 g, 1.1 mol) in 300 mL of dichloromethane was added dropwise over 30 minutes while maintaining the reaction mixture at 0 to 5° C. Then 20% aqueous potassium carbonate solution (450 g, 0.65 mol) was added dropwise over 30 minutes while keeping reaction temperature between 0 and 5° C. The reaction mixture was stirred for an additional 30 minutes at 0° C., and then allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined dichloromethane layers were concentrated under reduced pressure to yield a solid, which was triturated with 400 mL of hexanes. The slurry was filtered, and the filter cake was washed with 100 mL of hexanes and dried in a vacuum oven overnight at 50° C. to give 185.5 g of 1-(2-chloroacetyl)-N-(1,1-dimethylethyl)-4-piperidinecarboxamide as a solid, melting at 140.5-141.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]2[OH:12].Cl[S:17]([C:20]1[CH:21]=[C:22]([S:28]([F:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27])(=[O:19])=[O:18].CN(C)C1C=CC=CC=1.Cl>CN(C)C(=O)C>[F:31][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([S:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]3[OH:12])(=[O:18])=[O:19])[CH:21]=1)(=[O:29])=[O:30]
Reactant: Nc1cccc2c(O)c(C(=O)O)ccc12
Reactant: COc1ccc(S(=O)(=O)F)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(S(=O)(=O)F)cc1S(=O)(=O)Nc1cccc2c(O)c(C(=O)O)ccc12
Temperature: 22 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
5-Amino-1-hydroxy-2-naphthoic acid (10.2 g, 50 mmol) and 3-chlorosulfonyl-4-methoxybenzenesulfonylfluoride (14.4 g, 50 mmol) as prepared as in 1A were suspended in N,N-dimethylacetamide (100 ml). N,N-Dimethylaniline (15.1 g, 125 mmol) was added, the mixture was stirred at room temperature (22° C.) for 16 hours, and was then poured into ice water (750 ml) acidified with concentrated hydrochloric acid (25 ml). The mixture was extracted with three portions of ethyl acetate (500 ml each). The combined extracts were dried over anhydrous magnesium sulfate, the salts were removed by filtration, and the filtrate was decolorized with acidic alumina. The alumina was separated and the solvent was removed under reduced pressure to yield 8.3 g, (36.4%) of product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[CH:2]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: OCc1ccc(-c2cccnc2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: O=Cc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of (4-pyridin-3-yl-phenyl)-methanol (20 mg in 1.0 mL methylene chloride) was added 25 mg 4-methylmorpholine N-oxide, 20 mg 4 Å molecular sieves and 4 mg tetrapropylammonium perruthenate and the mixture stirred at room temperature. After 2 hours, the mixture was applied to a silica gel column and purified by flash chromatography (hexane:ethyl acetate, 40:60; then 60:40) to give the title compound (11.2 mg).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.C(O)C.O.[NH2:26]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:26]
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, 200 parts by volume of ethanol and 2.4 parts by volume of glacial acetic acid is added with stirring 5 parts by volume of 80% hydrazine hydrate. The mixture is stirred for 30 minutes at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine is yielded as reddish, viscous oily substance.
Reaction SMILES: Cl.[C:2]1([C@H:8]([NH:10][C@H:11]([CH3:22])[CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:21][CH2:20][CH2:19][C:15]1[CH:14]=[C:13]([CH2:12][C@H:11]([NH:10][C@@H:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])[CH3:22])[CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](Cc1cccc(CC#N)c1)N[C@H](C)c1ccccc1
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: C[C@H](Cc1cccc(CCN)c1)N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of {3-[(R)-2-((R)-1-phenylethylamino)propyl]phenyl}-acetonitrile hydrochloride salt (2.00 g, 6.35 mmol) and cobalt(II) chloride hexahydrate (4.27 g, 18.0 mmol) in MeOH (40.0 mL) at 0° C. was added sodium tetrahydroborate (2.72 g, 71.8 mmol) portion-wise (reaction was exothermic). The reaction mixture was stirred for 1 h at room temperature and then concentrated aqueous hydrochloric acid was added and stirring was continued until the solid that had formed was broken-up. The mixture was then made basic by addition of aqueous sodium hydroxide (1 M). This mixture was filtered and the filtrate was extracted with DCM (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which as used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:25]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 35.5 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:20][CH3:21])[S:13][C:14]=2[C:15]([O:17]CC)=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:20][CH3:21])[S:13][C:14]=2[C:15]([OH:17])=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1sc(NC)nc1C(C)c1ccc(-c2ccc(F)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1nc(C(C)c2ccc(-c3ccc(F)cc3)c(F)c2)c(C(=O)O)s1
Yield: 64.5 %

Procedure:
Ethyl 4-(1-(2,4'-difluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarboxylate (1.00 g, 2.48 mmole) was dissolved in methanol (20 ml). After adding a solution of potassium hydroxide (420 mg, 7.49 mmole) in water (4 ml), the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and washed with ether. The water layer was acidified to about pH 4 with 1chloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure Recrystallization of the residue from methanol gave the desired 4-(1-(2,4'-difluoro-4-biphenylyl-)ethyl)-2-methylamino-5-thiazolecarboxylic acid (599 mg, 1.60 mmoles, yield 65%) as a white crystalline product.
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1OCCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccccc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
3-(2-Isopropylphenoxy)propionic acid tert-butyl ester (10) (4.3 g) was dissolved in dichloromethane (40 mL), and to the mixture was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 3 h, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain the compound (11) 3.14 g.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][O:17][C:18]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[NH:21].[Na].Cl>C(O)C>[O:13]=[C:11]1[NH:22][C:20]([C:19]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=2[O:17][CH3:16])=[N:21][CH:4]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(C(=N)N)c(OC)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(OC)cc2OC)[nH]c1=O
Temperature: 0 °C
Yield: 76.2 %

Procedure:
A solution of diethyl ethoxymethylenemalonate (8.4 g., 0.0388 mole) in ethanol (20 ml.) was added dropwise to a cooled (ice-water) stirred mixture of 2,4-dimethoxybenzamidine (7.0 g., 0.0388 mole) in ethanol (50 ml.) containing sodium (0.89 g., 0.0388 g-atom). The mixture was heated under reflux for two hours. The cooled mixture was poured into ice-water and acidified with dilute hydrochloric acid. The precipitate was recrystallized from 95% ethanol to give ethyl 1,6-dihydro-6-oxo-2-(2,4-dimethoxyphenyl)pyrimidine-5 -carboxylate (9.0 g., 63.5% yield), m.p. 190°-192°.
Reaction SMILES: [Br-].[NH2:2][C:3]1[N:4]([CH2:20][C:21](=[O:27])[C:22]2[S:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[N+:7]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.[CH3:29][C:30](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>>[CH3:29][C:30]1[N:2]=[C:3]2[N:4]([C:20]=1[C:21](=[O:27])[C:22]1[S:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[N:7]2[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1n(CC(=O)c2cccs2)c2ccccc2[n+]1CCN1CCCCC1
Agent: [Br-]
Solvent: O
Product: Cc1nc2n(CCN3CCCCC3)c3ccccc3n2c1C(=O)c1cccs1

Procedure:
The bromide obtained in Step A is heated at reflux in 15 ml of acetic anhydide until completely dissolved. Cool and pour into 50 ml of cold water. Neutralise with a solution of sodium carbonate and extract twice with 10 ml of chloroform each time. Combine the organic phases, pass over a column of alumina and evaporate. Recrystallise the residue from ethyl acetate.