Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[C:27]([CH3:44])([CH3:43])[C:26]1=[O:45]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]6[C:27]([CH3:43])([CH3:44])[C:26](=[O:45])[N:25]([CH3:24])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CN1C(=O)C(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)C(C)(C)C(=O)N5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1,3,3-trimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Stage 233.1.1) to give the title compound as a white solid. (HPLC: tR 2.53 min (Method A); M+H=468 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.29 (m, 1H), 8.14-8.09 (m, 2H), 7.96-7.91 (m, 1H), 7.79-7.76 (m, 1H), 7.54-7.51 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.18 (s, 3H), 1.96 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H))
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[CH:4]=1)=[O:2].I[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH2:31])[N:24]([CH:32]([CH3:34])[CH3:33])[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]([CH3:34])[CH3:33])[N:23]=[C:22]([C:8]3[S:7][C:6]4[CH:19]=[CH:20][C:3]([CH:1]=[O:2])=[CH:4][C:5]=4[CH:9]=3)[C:30]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2cc3cc(C=O)ccc3s2)OC1(C)C
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cc3cc(C=O)ccc3s2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 45 %

Procedure:
A solution of 5-Formylbenzo[b]thiophene-2-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA42 (15.2 mg, 45% yield). ESI-MS (M+H)+ m/z calcd 338.1, found 338.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:8]=[C:9]([CH2:22]O)[CH:10]=[CH:11][C:12]=2[C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:22][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:8]=1
Reactant: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(CCl)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol T8.3 (34.5 mg, 105 μmol) was added DCM (1.1 mL) and DMF (8.2 μL, 105 μmol) followed by thionyl chloride (15 μL, 211 μmol) in an ice bath. The reaction was then stirred at room temperature for 1 hour. The reaction was concentrated and directly purified on silica gel to afford 4-(4-(chloromethyl)-2-(5,5-dimethylcyclopent-1-enyl)phenyl)-5-fluoro-2-methoxypyridine T8 (36 mg) as an oil (99%).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:26]([CH:32]4[CH2:34][CH2:33]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:29]1([C:28]2[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:6]5[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]5=[O:7])=[N:14][CH:13]=4)=[O:16])[CH2:22][CH2:21]3)=[N:24][CH:25]=[C:26]([CH:32]3[CH2:34][CH2:33]3)[CH:27]=2)[CH2:30][CH2:31]1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC1CCC(=O)N1
Product: CC1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cn1
Yield: 2987.4 %

Procedure:
Using 5-methylpyrrolidin-2-one (99 mg) and (6-bromopyridin-3-yl) [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (4.27 mg) described in Preparation Example 143 and by the reaction and treatment in the same manner as in Example 1, the title compound (133 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:20][CH:19]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 102 mg, 0.49 mmol) and 4-methoxy-benzyl bromide (73 μL, 0.50 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature overnight, then heated to 100° C. and left over the weekend. At this time it was found that the heating bath had failed and the reaction mixture was at room temperature. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-methoxy-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (48 mg, 30%) as a white solid. APCI-MS (M+H) 327.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:7]#[N:8])([O-:3])=[O:2].[H-].[Na+].I[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:16][CH2:17][CH3:18])[C:7]#[N:8])([O-:3])=[O:2]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 9 h

Procedure:
In DMF (15 ml), 3-nitro-4-aminobenzonitrile (500 mg) was dissolved, and the solution was added with sodium hydride (135 mg), followed by stirring at room temperature for 9 hours. The solution was added with 1-iodopropane (328 ml) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with water and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform), thereby obtaining the subject compound (362 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cc(O)ccc1F
Reactant: CCCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(Oc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 88 h
Yield: 76.4 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methylphenol (0.303 g, 2.404 mmol) in 15 mL of DMF, was added K2CO3 (1.661 g, 12.020 mmol). After stirring at room temperature under N2 for 88 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined and dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes to give the title compound as yellow oil (0.467 g, 76% yield). LC-MS: tR=10.5 min; m/z 255 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(=O)=O.[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>C(OCC)(=O)C>[CH3:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CS(=O)(=O)OCCCN1CCOCC1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(OCCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A flask was charged with 3-morpholinopropyl methanesulfonate (1.5 g, 6.9 mmol), 3-methyl-4-nitrophenol (0.96 g, 6.3 mmol), cesium carbonate (4.0 g, 12 mmol) and DMA (100 mL), and the reaction mixture was heated to 90° C. for 15 hours. Ethyl acetate (200 ml) was added to the cooled reaction mixture, and the mixture was extracted with water (2×100 ml), 1N sodium hydroxide (2×50 ml) and aqueous 5% lithium chloride (2×50 ml). The organic solvent was removed on a rotary evaporator under reduced pressure. Purification of the crude product by silica column chromatography using 50:50 ethyl acetate:hexanes as eluant gave 0.75 g of 4-(3-(3-methyl-4-nitrophenoxy)propyl)morpholine. (39% yield). MS (EI): 281 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.IC.[C:33](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:33])[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1
Reactant: C=CCOCC1(c2ccccc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.86 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile and 0.26 mL of iodomethane in 30 mL of DMF is added 430 mg of potassium carbonate. The mixture is stirred at rt for 5 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired product.
Reaction SMILES: [CH2:1]([C:5]12[CH2:21][C:20](=[O:22])[CH:19]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([Cl:15])[C:10]([O:16]C)=[C:9]([F:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4].[Br:23]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C=O)C>[Br:23][C:19]1[C:20](=[O:22])[CH2:21][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([F:18])=[C:10]([OH:16])[C:11]=3[Cl:15])[C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC12CCc3c(cc(F)c(OC)c3Cl)C1=CC(=O)C2
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCC12CCc3c(cc(F)c(O)c3Cl)C1=C(Br)C(=O)C2
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of 3a-butyl-6-chloro-8-fluoro-7-methoxy-3,3a,4,5-tetrahydro-cyclopenta[a]naphthalen-2-one (22 mg, 0.07 mmol) in DMF (0.12 mL) was treated with N-bromosuccinimide (12 mg, 0.07 mmol) at room temperature under N2 for 100 minutes, after which very little reaction had occurred. The reaction was thus heated to 60° C. for 50 minutes, then diluted with DMF (0.5 mL). Lithium chloride (29 mg, 0.68 mmol) was added and the reaction was heated to 100° C. After stirring at 100° C. for 1.5 hours the reaction was heated at 120° C. for 50 minutes. The reaction was cooled to room temperature and then partitioned between EtOAc/H2O. The organic portion was washed several times with water, then with brine, dried over MgSO4, filtered and then concentrated under vacuum. The crude material was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 2.5% MeOH in CH2Cl2. The low Rf band was eluted with 5% MeOH in CH2Cl2 and concentrated under vacuum to give 1-bromo-3a-butyl-6-chloro-8-fluoro-7-hydroxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an off-white film.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)(C)N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.00 g, 7.29 mmol) in DMA (18 ml) at room temperature was added tert-butylamine (2.4 ml, 22.03 mmol) and DIPEA (4.0 ml, 22.90 mmol). The reaction mixture was heated to 50° C. and stirred for one day. The temperature was increased to 70° C. and the reaction mixture was stirred for two days. The temperature was further increased to 120° C. and the reaction mixture was stirred for 8 h. The reaction mixture was then transferred into a sealed vial, additional tert-butylamine (1 mL, 9.18 mmol) was added and the mixture was continued to stir at 120° C. for another 4 days. The crude mixture was concentrated and purified by column chromatography on silica gel using a gradient of MeOH (0-3%) in DCM to yield the title compound as a white solid mixed with a brown liquid. The material was dissolved in DCM and aqueous citric acid (<10%). Layers were separated, the aqueous layer was washed with DCM.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Br)o1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Br)o1

Procedure:
59.3 Using general method H, 5-bromo-furan-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-bromo-furan-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 504.9 ([M+H]+)
Reaction SMILES: [Br:1]C1C(Cl)=C(CC2C=CC(OCC)=CC=2)C=C([C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](OCC3C=CC=CC=3)[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O2)C=1O.[CH2:59]([C:66]1[C:67]([Cl:112])=[C:68]([OH:111])[CH:69]=[C:70]([C@H:72]2[C@H:77]([O:78][CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C@@H:76]([O:86][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)[C@H:75]([O:94][CH2:95][C:96]3[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=3)[C@@H:74]([CH2:102][O:103][CH2:104][C:105]3[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=3)[O:73]2)[CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([C:66]1[C:67]([Cl:112])=[C:68]([OH:111])[C:69]([Br:1])=[C:70]([C@H:72]2[C@H:77]([O:78][CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C@@H:76]([O:86][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)[C@H:75]([O:94][CH2:95][C:96]3[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=3)[C@@H:74]([CH2:102][O:103][CH2:104][C:105]3[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=3)[O:73]2)[CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Reactant: Oc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccccc2)c1Cl
Product: Oc1c(Cl)c(Cc2ccccc2)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1Br

Procedure:
Similar procedure with preparation of 28 proceeded except for using compound 170 to obtain the compound 171.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[NH:20][CH2:21][CH3:22])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25](OCC)=[O:26].C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:1]([N:8]1[C:25](=[O:26])[CH2:24][S:10][C:9]1=[N:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[NH:20][CH2:21][CH3:22])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1NC(=S)NCc1ccccc1
Reactant: CCOC(=O)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a 100 mL flask was added 1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.0 g, 3.2 mmol), anhydrous ethanol (40 mL), ethyl chloroacetate (0.39 g, 3.2 mmol) and then DBU (0.58 g, 3.8 mmol). The reaction was heated at 80° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex) to afford the title product (0.98 g, 87%). 1H-NMR (CDCl3): δ 7.38 (6H, m), 7.11 (1H, d), 6.50 (1H, d), 5.05 (2H, s), 3.96 (2H, s), 3.01 (2H, m), 1.03 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22]([O:24]CC3C=CC=CC=3)=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:40](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.[Pd]>[C:22]([N:21]([CH3:32])[CH2:20][CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15]1=[O:33])(=[O:24])[CH3:40]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.023 g, 0.043 mmol) in CH2Cl2 (1.5 mL) was combined with diisopropylethylamine (0.0038 mL, 0.22 mmol), acetic anhydride (0.021 mL, 0.22 mmol) and Pd/C (0.012 g, 10% w/w). The resulting suspension was flushed with nitrogen and evacuated several times the charged with hydrogen under a balloon and stirred at ambient temperature overnight. The reaction mixture was filtered, washed with CH2Cl2, and concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with 1N NaHSO4, and brine, concentrated the organics to afford the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.59 Hz, 3 H), 1.86 (s, 3 H), 2.94 (s, 3 H), 3.50 (t, J=6.86 Hz, 2 H), 4.18 (s, 2 H), 4.28 (q, J=6.83 Hz, 4 H), 7.12 (t, J=8.69 Hz, 2 H), 7.35-7.40 (m, 2 H), 8.02 (d, J=6.40 Hz, 1 H), 8.47 (s, 1 H); ES+ MS: 442 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:2]=1.[C:16](O)(=O)C.C=O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=1
Reactant: NCCc1csc(Nc2cccnc2)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: c1cncc(Nc2nc3c(s2)CNCC3)c1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
2-(3-Pyridyl)amino-4-(2-aminoethyl)thiazole (0.50 g, from preceding preparation) and acetic acid (0.19 ml, 3.3 mmol) were dissolved in methanol (23 ml) and treated with formaldehyde (0.19 ml of a 37% aqueous solution, 2.3 mmol). The reaction was allowed to stir at room temperature for 18 hours, at which point additional formaldehyde (0.02 ml of a 37% aqueous solution, 0.25 mmol) was added. After an additional 2 hours, the reaction mixture was filtered; the filtrate was concentrated in vacuo, dissolved in aqueous base, and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated to provide the title product (310 mg, 1.3 mmol, 57% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([CH:9]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:10])=[CH:7][N:8]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:6]=1[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2
Reactant: CSc1ncc(C(C)NC(=O)c2ccccc2)nn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Yield: 63.5 %

Procedure:
Applying the Cyclization Procedure 1, using N-{1-[3-(methylthio)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 70) (590 mg, 2.15 mmol), 1,2-dichloroethane (10 mL) and phosphorus oxychloride (1.60 mL, 17.17 mmol), to afford 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (350 mg) as a yellow solid. MS m/z 257 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][O:7][CH2:8]Cl.Cl.[Cl:16][C:17]1[CH:18]=[N:19][C:20](=[O:23])[NH:21][CH:22]=1>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][O:7][CH2:8][N:21]1[CH:22]=[C:17]([Cl:16])[CH:18]=[N:19][C:20]1=[O:23]
Reactant: FC(F)(F)c1cccc(COCCl)c1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Product: O=c1ncc(Cl)cn1COCc1cccc(C(F)(F)F)c1

Procedure:
was prepared as described in Example 3 from chloromethyl 3-trifluoromethyl-benzyl ether (see Preparation 6a and 6b) (10 mmol) and 5-chloropyrimidin-2-one hydrochloride (10 mmol) in 52%. (1.66 g) yield, m.p. 95° C. 1H NMR (CDCl3): δ4.77 (CH2Ph), 5.42 (CH2O), 7.3-7.7 (Ph), 7.82 and 8.55 (H-4, H-6, J 4 Hz). IR(KBr): 1660 cm-1 (CO).