Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=O)[CH2:14][C:15](=O)[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27]>>[NH2:28][C:26]1[N:27]=[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[CH:14]=[C:15]([CH:16]([CH3:18])[CH3:17])[N:25]=1
Reactant: N=C(N)N
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)c2ccc(F)cc12
Agent: O=C(O)O
Product: CC(C)c1cc(-c2ccc(F)c3ccc(F)cc23)nc(N)n1
Temperature: 150 °C
Yield: 34.7 %

Procedure:
1-(4,7-difluoronaphth-1-yl)-4-methylpentane-1,3-dione (0.114 g, 0.5 mmol) was combined with guanidine carbonate (0.180 g, 0.5 mmol) and heated to 150° C. for 6 hours. The reaction was cooled to room temperature and directly purified by column chromatography to give 2-amino-4-(4,7-difluoronaphth-1-yl)-6-isopropylpyrimidine (0.052 g, 34%), m.p. 103°-105° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:34]([N:37]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[N:38]1)([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:39]3[CH:40]=[CH:41][N:37]([CH:34]([CH3:36])[CH3:35])[N:38]=3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Product: Cc1c(Cc2ccc(-c3ccn(C(C)C)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 22b using [3-(4-bromobenzyl)-8-chloro-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid tert-butyl ester and 1-isopropyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [Mg].CI.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)Oc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: C[Si](C)(C)Oc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
5.35 g (0.22 mole) magnesium was added to 10 ml tetrahydrofuran and 0.35 ml CH3I under N2 and heated to initiate the Grignard reaction. A solution of 49.0 g (0.2 mole) p-bromophenyoxytrimethylsilane and 63 ml tetrahydrofuran was added over a 11/2 hour period. The reaction mixture was refluxed one additional hour and then cooled to room temperature. 22.8 g (0.21 mole) chlorotrimethylsilane was added to the reaction mixture. Once again the mixture was refluxed 1 hour and then cooled. 100 ml distilled water was slowly added, stirred, and separated. The organic phase was washed with two 50 ml portions of water and finally 50 ml of brine. The organic solution was dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator under reduced pressure. Vacuum distillation gave 28.7 g of p-trimethylsilylphenoxytrimethylsilane, bp 132 degrees Celsius at 27 mm Hg.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:20]([NH2:28])=[O:27])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Yield: 93.6 %

Procedure:
4-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-ylamine (193 mg, 0.73 mmol) is dissolved in DCM (7 mL) and benzoyl isocynate (215 mg, 1.46 mmol) is added. The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (7 mL) and potassium carbonate (151 mg, 1.10 mmol). The mixture is heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (45 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 210 mg of the desired product.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:10]([C@@H:11]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]3)[C:9]2=[O:26])C(=O)C2=CC=CC=C12.O.NN>CCO>[NH2:5][CH2:6][CH2:7][N:8]1[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:10]([C@@H:11]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)[C:9]1=[O:26]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN)c1=O

Procedure:
A solution of 100 mg 3-PHT-E-AZT (Example 25) in 1 ml absolute EtOH was treated with 25 ul hydrazine hydrate, incubated overnight at room temperature and chromatographed by preparative TLC on silica gel-F 1000 um using the solvent system CHCl3 /MeOH/15M NH4OH (90+10+1). The UV positive band at Rf =0.25 was eluted with MeOH. Analytical TLC of the methanol extract in the same solvent system with silica gel-F 250 um showed the product to be homogeneous and ninhydrin positive. In this system a hydrazine reference migrated close to the origin as a UV negative, ninhydrin positive spot and reference phthalhydrazide remained at the origin as a UV positive, ninhydrin negative spot.
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=[O:6])[CH2:3][CH2:2]1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH2:23])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH:23][C:5](=[O:6])[CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CC1CC1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)CC2CC2)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopropylacetyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 27% yield; m.p. 136-139° C.; 1H NMR (CDCl3, 300 MHz) δ 7.34-7.24 (m, 5H), 5.97 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.60 (s, 3H), 2.39 (d, J=7.2 Hz, 2H), 1.05-1.00 (m, 1H), 0.71-0.68 (m, 2H), 0.27 (q, J=4.8 Hz, 2H); MS (ES+) m/z 330.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1.Cl>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 146 was prepared from bis(4-fluorophenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 2H), 7.30–7.19 (m, 4H), 7.11–7.07 (m, 1H), 7.01–6.96 (m, 5H), 6.88 (d, 1H, J=7.7 Hz), 6.69 (s, 1H), 4.97 (septet, 1H, J=6.3 Hz), 4.79 (s, 1H), 4.11 (q, 1H, J=6.8 Hz), 3.39 (q, 2H, J=5.6 Hz), 2.98–2.92 (m, 2H), 2.52–2.40 (m, 3H), 1.98 (t, 2H, J=11.5 Hz), 1.85–1.78 (m, 2H), 1.72–1.54 (m, 3H), 1.27 (d, 6H, J=6.3 Hz); ESMS m/e: 550.3 (M+H)+; Anal. Calc. for C32H37F2N3O3.0.87 HCl: C, 66.84; H, 6.61; N, 7.31.Found: C, 66.83; H, 6.48; N, 7.31.
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@H:9]([C:14]1[CH:23]=[C:22]2[C:17]([O:18][CH2:19][C:20](=[O:24])[NH:21]2)=[N:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])C1C=CC=CC=1>CCO.O.CC(O)=O>[C:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH2:8])[C:14]1[CH:23]=[C:22]2[C:17]([O:18][CH2:19][C:20](=[O:24])[NH:21]2)=[N:16][CH:15]=1)([CH3:23])([CH3:15])[CH3:9]
Reactant: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)O)c1cnc2c(c1)NC(=O)CO2
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](N)c1cnc2c(c1)NC(=O)CO2
Reaction time: 18 h

Procedure:
A mixture of the dibenzylamine 20-6 (0.22 g, 0.44 mmol) in EtOH/H2O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (100 mg). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (20% 20:1:1 EtOH/NH4OH/H2O-80% EtOAc) to give the tert-butyl ester 20-7 as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8]2)[N:6]=1.[C:15]([C:17]1([NH:20][C:21](=[O:49])[C@H:22]([CH2:44][C:45]([F:48])([CH3:47])[CH3:46])[NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[C:25]([F:28])([F:27])[F:26])[CH2:19][CH2:18]1)#[N:16]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:15]([C:17]1([NH:20][C:21]([C@@H:22]([NH:23][C@@H:24]([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[S:3][CH:4]=[C:5]([C:7]4([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]4)[N:6]=3)=[CH:33][CH:34]=2)[C:25]([F:26])([F:28])[F:27])[CH2:44][C:45]([F:48])([CH3:47])[CH3:46])=[O:49])[CH2:19][CH2:18]1)#[N:16]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: CCOC(=O)C1(c2csc(Br)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2nc(C3(C(=O)O)CC3)cs2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 80 °C

Procedure:
A solution of ethyl 1-(2-bromo-1,3-thiazol-4-yl)cyclopropanecarboxylate (166 mg, 1.2 mmol) and N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-L-leucinamide (Example 3, Step 3, 250 mg, 0.5 mmol) in DMF (5 mL) and 2M Na2CO3 (0.63 mL) was degassed with a stream of nitrogen for 10 min, then PdCl2(dppf) (41 mg 0.05 mmol) was added and the mixture heated to 80° C. for 8 h. The mixture was cooled and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was washed with brine, dried over MgSO4 and evaporated. Purification by SiO2 chromatography (30% ethyl acetate/hexanes) provided the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][NH:7]1)=[O:5])C.[ClH:27]>>[ClH:27].[ClH:27].[CH2:25]([O:24][C:22]([C:20]1[N:19]=[CH:18][N:17]([CH2:16][C@H:12]2[CH2:11][CH2:10][C@@H:9]3[C@@H:14]([CH2:15][C@@H:6]([C:4]([OH:5])=[O:3])[NH:7][CH2:8]3)[CH2:13]2)[CH:21]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cn(C[C@H]2CC[C@H]3CN[C@H](C(=O)OCC)C[C@H]3C2)cn1
Agent: Cl
Product: CCOC(=O)c1cn(C[C@H]2CC[C@H]3CN[C@H](C(=O)O)C[C@H]3C2)cn1
Reaction time: 18 h

Procedure:
A solution of 0.20 g of [3S,4aR,6S,8aR]-ethyl-6-((4-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (prepared in example 3) in 10 mL of 5N HCl was heated at 50° C. for three hours and then at room temperature for 18 h. The solution was evaporated and the resulting residue was chromatographed over C18 modified silica gel eluting with acetonitrile in aqueous 0.1% HCl to give 0.105 g of the title compound: MS m/z: 336 (m++1); Analysis calculated for C17H25N3O4HCl1.5H2O: C, 51.2; H, 7.35; N, 10.55. Found: C, 51.33; H, 7.04; N, 10.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N+:22]([O-:24])=[O:23])=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34].Cl>CN(C=O)C>[OH:34][CH2:33][CH2:32][N:9]1[C:8]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:7]([N+:22]([O-:24])=[O:23])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: OCCBr
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2[N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c([N+](=O)[O-])c3ccc(OC)cc3c(=O)n2CCO)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
In a 25-mL flask under argon, 7-methoxy-3-(4-methoxyphenyl)-4-nitroisoquinoline-1(2H)-one (compound D5, 150 mg, 0.46 mmol) is dissolved in 5 mL of DMF. Potassium carbonate (317 mg, 2.3 mmol) is then added. After stirring for 30 minutes, 2-bromoethanol (329 μl, 4.6 mmol) is added. Stirring is maintained for 24 hours at 50° C. Once returned to ambient temperature, the medium is neutralized with 20 mL of a 1N hydrochloric acid solution then extracted with 3×10 mL of ethyl acetate. The organic phases are washed with 3×10 ml of H2O, dried over MgSO4 and concentrated under vacuum. The residue obtained is chromatographed on a silica gel column using the cyclohexane-ethyl acetate mixture (60/40) as eluent in order to produce the expected 2-(2-hydroxyethyl)-7-methoxy-3-(4-methoxyphenyl)-4-nitroisoquinoline-1(2H)-one 68 (73 mg, 43%) in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1.CCN(CC)CC.Cl>CN(C=O)C.O>[OH:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[CH2:18][CH2:19]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(trifluoromethoxy)phenyl isocyanate (2 g, 9.8 mmol) in DMF (100 mL) were added trans-4-aminocyclohexanol hydrochloride (1.6 g, 10.8 mmol) and Et3N (1.5 mL, 10.8 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred overnight. After adding aq 1N HCl (20 mL) and water (100 mL), the resulting white precipitates were collected by suction filtration. The collected solid was thoroughly washed with water. Recrystallization from acetone at −78° C. afforded 2.4 g (70%) of the title compound as a white solid. mp 224.1-225.3° C. 1H NMR (300 MHz, DMSO-d6; δ 8.50 (s, 1H), 7.45 (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz, 2H), 6.06 (d, J=8 Hz, 1H), 4.55 (d, J=4 Hz, 1H), 3.44-3.33 (m, 2H), 1.91-1.68 (m, 4H), 1.31-1.07 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22](O)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:26])([CH3:25])[C:12]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C@@H:36]1[C@@H:41]([C:42]2[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=2[F:50])[CH2:40][CH2:39][N:38]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:37]1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([NH:35][C@@H:36]3[C@@H:41]([C:42]4[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=4[F:50])[CH2:40][CH2:39][N:38]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:37]3)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:26])([CH3:25])[C:12]1=[O:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](N)C1
Reactant: CC1(C)Oc2cc(F)c(C(=O)O)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)c2cc3c(cc2F)OC(C)(C)C(=O)N3CCN(Cc2ccccc2)Cc2ccccc2)C1

Procedure:
Using 4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3R,4R)-3-amino-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[C:22]3[N:21]=[CH:20][N:19]([CH3:23])[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[NH3:24]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[C:22]3[N:21]=[CH:20][N:19]([CH3:23])[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc2c1ncn2C
Reactant: N
Product: Cn1cnc2c(Nc3cc(Cl)nnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate (285 mg, 859 μmol) was suspended in ammonia (7M in methanol, 7.87 g, 10.0 mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 18 h. The solvent was evaporated and the residue dried in high vacuum to give 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxamide (260 mg, 100%) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.36 (s, 1H), 8.74 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.41-7.52 (m, 1H), 7.28-7.35 (m, 2H), 7.23 (s, 1H), 3.86 (s, 3H); LC-MS 303.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:31])=[CH:22][C:23]=2C2C=CC=CC=2Cl)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[C:39]([CH3:46])[CH:38]=1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:31])=[CH:22][C:23]=2[C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]=2[CH3:46])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:34])([F:35])[F:1])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: Cc1cc(F)ccc1B(O)O
Product: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared according to the procedures described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 24) using (4-fluoro-2-methylphenyl)boronic acid instead of 2-chlorophenylboronic acid in step c).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC#N.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3cccs3)cc12
Temperature: 90 °C
Yield: 39.1 %

Procedure:
A mixture of 8 (50.0 mg, 0.128 mmol), 2-(tributylstannyl)thiophene (88 μL, 0.276 mmol), dichlorobis(acetonitrile)palladium (II) (4.0 mg, 0.0138 mmol), tri-o-tolylphosphine (8.0 mg, 0.0276 mmol) and toluene (1.0 mL) were heated at 90° C. overnight. The mixture was separated by PTLC using ethyl acetate:hexane (3:7) as eluent to give 11 as a white solid (18.3 mg, 36%); 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.1 Hz, 1H), 8.28 (m, 3H), 8.16 (d, J=2.1 Hz, 1H), 7.68 (tt, J=7.5, 1.2 Hz, 1H), 7.57 (t, J=4.1 Hz, 2H), 7.37 (m, 2H), 7.13 (dd, J=5.1, 3.6 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].FC1C=CC(I)=C(C=1)C(O)=O>>[N:12]1[N:11]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting 2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.91 (s, 2H), 7.85-7.82 (m, 1H), 7.75 (dd, J=8.1, 1.0 Hz, 1H), 7.69 (td, J=7.7, 1.5 Hz, 1H), 7.60-7.55 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH2:18][CH2:19][CH2:20]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
A mixture of 4-chlorophenylboronic acid (167 mg), 4-(2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (100 mg), pyridine (0.087 mL), diacetoxycopper (130 mg), and cesium carbonate (116 mg) in DMSO (3.0 mL) was stirred at room temperature for 24 hr. The mixture was diluted with water, and extracted with EtOAc (40 mL). The organic layer was washed with 0.1N NaOH aq. (2×40 mL) and then brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give the title compound (23.0 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:23][C:24](=[N:27][CH3:28])SC)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:23][C:24]([NH:27][CH3:28])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)SC
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.49 g.) and N-(3.4-dichlorobenzenesulphonyl)-N', S-dimethylisothiourea (6.20 g.) in acetonitrile (250 ml.) was heated under reflux for 48 hours. Concentration, followed by chromatographic purification on a column of alumina with sequential elution by benzene-ethylacetate (1:4) and benzene-ethanol (1:4) afforded N-(3,4-dichlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] guanidine as a glass (1.7 g.)
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[N:23][C:22]([NH2:30])=[CH:21]2>ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[N:23][C:22]([N:30]=[C:1]=[S:2])=[CH:21]2
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc2cnc(N)cc2cc1Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2cnc(N=C=S)cc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (142 mg, 0.611 mmol) in dichloromethane (5 mL) was added a suspension of 6-chloro-7-methoxyisoquinolin-3-amine (110 mg, 0.527 mmol) in dichloromethane (5.00 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was applied directly to a silica gel column in 10% ethyl acetate/hexane to yield 106 mg (80%) 6-Chloro-3-isothiocyanato-7-methoxyisoquinoline. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.90 (1H, s), 7.99 (1H, s), 7.36 (1H, s), 7.08 (1H, s), 4.05 (3H, s).