Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[NH2:22]>C(O)C>[F:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][C:17]=1[F:21])[N:22]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([OH:10])=[N:13]2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CCO
Product: CCOC(=O)c1nc2cc(F)c(F)cc2nc1O

Procedure:
A suspension of diethyl ketomalonate (1.11 mL, 7.3 mmol) and 1,2-diamino-4,5-difluorobenzene (1.0 g, 6.9 mmol) in anhydrous ethanol (20 mL) was heated at reflux under nitrogen for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/methylene chloride (1:2), to provide ethyl 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylate as a light yellow solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:13]I>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:13])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#CCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C#N)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 54.9 %

Procedure:
To a solution of 3-bromophenylacetonitrile (12 g, 61.2 mmol) in tetrahydrofuran (150 ml) cooled down to 0° C., was added 60% sodium hydride in mineral oil (2.25 g, 56.3 mmol) portionwise over 10 minutes. The reaction mixture was stirred at 0° C. for 40 minutes. Methyl iodide (5.71 ml, 91.8 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for a further 1 hour. The reaction mixture was diluted with ethyl acetate (250 ml), washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion, 330 g column, 0-20% EtOAc/Petrol) to afford the title compound as a colourless oil (7.06 g, 55% yield).
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:14]([Cl:21])=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([OH:24])=[O:20])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: CC(C)=O
Reactant: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of diallyl 2-chloro-6-(hydroxymethyl)benzyl phosphate (2.62 g, 7.88 mmol) obtained from Example 27-(3) in acetone (25 ml) was cooled to 0° C., and Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 12 ml, ca. 32 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then 2-propanol (1 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and then the filtrate was concentrated under reduced pressure to give an oily residue. The residue was thoroughly dried using a vaccum pump, and then subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:dichloromethane=1:10˜1:1) to afford the title compound (2.065 g, 76% yield) as a pale brown oil.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:41][C:40]5[C:35](=[CH:36][C:37]([Cl:42])=[CH:38][CH:39]=5)[C:34]4=[O:43])[C:28]=2[CH3:44])=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([NH:17]C(=O)OCC[Si](C)(C)C)[CH:12]=3)(=[O:3])[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.CCOC(C)=O>O1CCCC1>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]3[C:7]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH2:41][C:40]6[C:35](=[CH:36][C:37]([Cl:42])=[CH:38][CH:39]=6)[C:34]5=[O:43])[C:28]=4[CH3:44])=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]=3[NH:10]2)=[CH:15][CH:14]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(NC(=O)OCC[Si](C)(C)C)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reaction time: 4 h

Procedure:
To a burgundy, homogeneous solution of 2-(trimethylsilyl)ethyl 1-carbamoyl-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate (0.126 g, 0.201 mmol) in tetrahydrofuran (0.2 mL) was added 1M TBAF/THF (0.402 mL, 0.402 mmol). After 4 hr, EtOAc (80 mL) was added, and the layer was washed with water (20 mL) and brine (20 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give a crude product as a light brown solid, which was used in the subsequent step.
Reaction SMILES: ClC1C([C:8](O)=[O:9])=C(C2C=CC=CC=2)C(C)=CN=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:23][NH:24][CH2:25]CCO>>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:22]([CH:21]=[C:20]([C:19]([F:37])([F:36])[F:18])[CH:31]=1)[CH2:23][NH:24][CH2:25][CH2:8][OH:9]
Reactant: OCCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cnc(Cl)c(C(=O)O)c1-c1ccccc1
Product: OCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-Chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid was used in place of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 in Reference Example 12, reacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine that had been obtained in Step 1 in Reference Example 23, in place of N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, and treated in the same manner as in Step 2 in Reference Example 12, to obtain the entitled compound as a pale yellow oil. NMR(200 MHz, CDCl3) ppm: 1.10-1.80(2H,m), 2.06(3H×1/2,s), 2.08(3H×1/2,s), 2.80-3.30(3H,m), 3.35-3.70(1H,m), 4.08(1H×1/2,d,J=16.4 Hz), 4.39(1H×1/2,d,J=15.0 Hz), 4.47(1H×1/2,d,J=16.4 Hz), 4.70(1H×1/2,d,J=15.0 Hz), 6.90-7.62(7H,m), 7.72(1H×1/2,s), 7.77(1H×1/2,s), 8.28(1H×1/2,s), 8.31(1H×1/2,s).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:33]1([CH2:32][O:31][C:29](=[O:30])[CH2:28][NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(N)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(NCC(=O)OCc2ccccc2)c1
Yield: 71.9 %

Procedure:
A mixture of 1.08 g (3.0 mmol) of 3-(octadecyloxy)benzenamine, 0.52 ml (3.3mmol) of benzyl bromoacetate and 0.8 g (6.0 mmol) of potassium carbonate in40 ml of acetone was stirred at reflux under argon for 18 hours. The reaction mixture was filtered and the filtrate was concentrated at reducedpressure to an oil which was purified by chromatography on 150 g of silica gel using 20% ethyl acetate-hexane to give 1.1 g (72% yield, mp 55°-60°) of N-[3-(octadecyloxy) phenyl]glycine phenylmethyl ester.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[C:29]1([CH2:35][CH2:36]C=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:36][CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: O=CCCc1ccccc1
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCc1ccccc1

Procedure:
The product of Example 84 is treated with 3-phenylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:5]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCN(CCO)CC2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCN(CCO)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.1 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)piperazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.2 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.18 g, 1.2 mmol) in ethanol (6.0 mL), piperidine (0.12 mL, 1.4 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.050 g, y. 10%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[CH2:10][C:9](=[O:11])[NH:8][C@H:7]2[CH2:12][CH2:13][CH2:14][CH2:15][C@H:6]2[NH:5]1.[CH2:17](I)[CH3:18]>O1CCOCC1>[CH2:17]([N:8]1[C@H:7]2[CH2:12][CH2:13][CH2:14][CH2:15][C@H:6]2[NH:5][C:4]([CH3:16])([CH3:3])[CH2:10][C:9]1=[O:11])[CH3:18]
Reactant: CCI
Reactant: CC1(C)CC(=O)N[C@H]2CCCC[C@H]2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1C(=O)CC(C)(C)N[C@@H]2CCCC[C@@H]21
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
1.25 g sodium hydride (50% in oil) was dissolved in p-dioxane in a 250 ml flask, and 4.15 g cis-4,4-dimethyl-decahydro-1,5-benzodiazepin-2-one added. The mixture is stirred for about 1.5 hr. and cooled. 5.0 g ethyl iodide dissolved in 5 ml dioxane was added and the mixture stirred at 55°-60° C. overnight. It is then cooled and the solvent is removed to yield 4.67 g of an oily product. The structure of the compound obtained is confirmed by IR, NMR and mass spectrometer data.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][CH2:19][C:20]([CH3:27])([NH2:26])[C:21]#[C:22][C:23]([OH:25])=O.[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1>O1CCCC1.N1C=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:23](=[O:25])[C:22]#[C:21][C:20]([CH2:19][CH2:18][O:17][CH3:16])([CH3:27])[NH2:26])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COCCC(C)(N)C#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCC(C)(N)C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2 mmol) and N-methylmorpholine (1.2 g, 11.9 mmol) were added to an ice cold solution of 1.6 g (9.52 mmol) of (2-methoxy-ethyl)-methyl-amino-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, then it was poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.560 g of (2-methoxy-ethyl)-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 468.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:16])[N:9]2[CH2:12][C:13]([OH:15])=O)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:13](=[O:15])[CH2:12][N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:17]([F:19])([F:18])[F:20])=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:16])[S:25][CH:26]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)c(F)cc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)c(F)cc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide was synthesized from 2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.276, method [7], MS(ESI) 516.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (b s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.20 (d, J=9.34 Hz, 1H), 7.89 (d, J=13.72 Hz, 1H), 7.31 (s, 1H), 6.81 (d, J=9.34 Hz, 1H), 5.28 (s, 2H).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:16][NH2:17].[BH4-].[Na+]>CO>[CH3:16][NH:17][CH2:1][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: O=CC1CCSc2[nH]c3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCC1CCSc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the product of the above (2) (2.17 g) in absolute methanol (10 ml) is added a 30% solution (2.2 ml) of methylamine in methanol. The mixture is stirred at room temperature for 1 hour. Sodium borohydride (380 mg) is added to the filtrate. The mixture is stirred at room temperature for 2 hours and evaporated to remove the solvent. The residue is acidified with 2 N hydrochloric acid after addition of water. The solution is extracted with chloroform to remove neutral impurities. The aqueous layer is made alkaline with an aqueous solution of sodium hydroxide and extracted again with chloroform. The extract is washed with water, dried and evaporated to remove the solvent. The residue is treated with small amount of benzene to give the 1/6 benzene adduct (2.21 g) of the title compound melting at 78°-81° C. Yield: 90%
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:23][CH2:22][CH:18]([C:19]([NH2:21])=[O:20])[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:15]2[CH2:23][CH2:22][CH:18]([C:19]([NH2:21])=[O:20])[CH2:17][CH2:16]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)C1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 66 %

Procedure:
Step 1): Bromodiphenylmethane (2.5 g, 0.01 mol) in DMF (10 ml) was added dropwise at 0°-5° C. to a mixture of isonipecotamide (1.3 g, 0.01 mol) and K2CO3 (1.4 g) in DMF (25 ml). The reaction mixture was stirred for 2 hours at 0°-5° C., then poured into water. The mixture was extracted with ethylether, then the extract was washed with brine, dried (MgSO4) and evaporated to give 1-diphenylmethylpiperidine-4-carboxamide (66%): mp 150° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[C:13](=[O:16])[CH2:14][O:15][C:11]=2[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>ClCCl>[Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[CH:13]([OH:16])[CH2:14][O:15][C:11]=2[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-tert-Butyldimethylsilyloxy-2,3-dihydrobenzofuran-3-one (42 g, 158 mmol) in dichloromethane (1.4 L) at −78° C. under nitrogen was slowly added a solution of DIBAL-H (238 mL, 1.0 M, 238 mmol) in dichloromethane. The reaction was stirred at −78° C. for 1 h, and then was quenched carefully with ethyl acetate (1.0 L). Cold bath was removed, and a solution of Rochelle's salt (400 mL, 10%) was added continuously with stirring over a period of 2 h. The mixture was then diluted with MTBE (4.0 L), washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the final product as yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:3]([C:5]2[N:6]=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])[NH:8][C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:24][CH:23]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Product: O=C(NCc1ccc(F)cc1)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Yield: 70.6 %

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmol) and 4-fluorobenzylamine (0.5 ml; 4.4 mmol). This gave the title compound as a white solid (0.072 g; 70%). LCMS: m/z=433 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:46][C:47]1[CH:60]=[CH:59][C:50]([O:51][C:52]2[O:56][C:55]([CH2:57][NH2:58])=[CH:54][CH:53]=2)=[CH:49][CH:48]=1>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:58][CH2:57][C:55]1[O:56][C:52]([O:51][C:50]2[CH:59]=[CH:60][C:47]([F:46])=[CH:48][CH:49]=2)=[CH:53][CH:54]=1)=[O:6]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NCc1ccc(Oc2ccc(F)cc2)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C(=O)NCc2ccc(Oc3ccc(F)cc3)o2)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
2,6-Diamino-nicotinic acid described in Preparation Example A-15 (0.15 g, 0.98 mmol), triethylamine (0.41 mL, 2.94 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.65 g, 1.47 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the solution was stirred at room temperature for 10 minutes. Then, a solution of C-(5-(4-fluoro-phenoxy)-furan-2-yl)methylamine described in Preparation Example 169 (304 mg, 1.47 mmol) in N,N-dimethylformamide (1 mL) was added thereto, followed by stirring at room temperature for 14 hours 50 minutes. After the reaction was completed, reaction solution was poured into brine, the solution was extracted with ethyl acetate, the fractionated organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was subjected to silica gel column chromatography, eluted with solvent (ethyl acetate), and the title compound (0.12 g, 0.35 mmol, 36%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].Br[N:11]1C(=O)CC[C:12]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C-]#N.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:11])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1

Procedure:
A solution of 1-bromo-2-fluoro-4-methyl-benzene (5.0 g, 26.45 mmol), N-bromosuccinimide (4.94 g, 27.75 mmol) and benzoyl peroxide (100 mg) in carbon tetrachloride (75 mL) was heated under reflux for 3 hrs, allowed to cool, filtered and the residue flashed through a plug of silica gel, eluting with hexanes. The solvent was evaporated to dryness to afford a colorless oil. The crude product (1.73 g, 6.46 mmol) and sodium cyanide (317 mg, 6.46 mmol) was heated to reflux in a mixture of ethanol (17 mL) and water (3 mL) for a period of 4 hrs. After cooling, the solution was evaporated to dryness and the residue purified by column chromatography (0 to 10% EtOAc in hexanes) to afford (4-bromo-3-fluoro-phenyl)-acetonitrile as a pale orange solid. 1H NMR (500 MHz, CDCl3) δ 7.56 (1H, m), 7.12 (1H, d, J=8.9 Hz), 7.02 (1H, d, J=8.9 Hz), 3.73 (3H, s).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[C:8]([C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12][CH:11]=1)=[CH:7][CH:6]=[N:5]2.[I:20]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:20][C:3]1[N:4]2[N:5]=[CH:6][CH:7]=[C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[N:12][CH:11]=3)[C:9]2=[N:1][CH:2]=1
Reactant: c1ccc2c(-c3ccnn4ccnc34)cncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Ic1cnc2c(-c3cncc4ccccc34)ccnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-(imidazo[1,2-b]pyridazin-8-yl)isoquinoline (220 mg, 0.893 mmol) in CHCl3 (10 mL) were added N-iodo succinimide (241 mg, 1.072 mmol) and TFA (0.275 mL, 3.57 mmol) In CHCl3 (1 mL). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated NaHCO3. The layers were separated and the combined organic layer was washed with water and brine, dried over Na2SO4. The crude product was purified by BIOTAGE® (30-70% EtOAc/CH2Cl2, 0.8 L) to give the product (290 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 9.41 (1H, s), 8.72 (1H, s), 8.66 (1H, d, J=4.53 Hz), 8.07-8.17 (1H, m), 7.90 (1H, s), 7.71 (3H, d, J=3.02 Hz), 7.28 (3H, s), 7.26 (1H, d, J=4.53 Hz); LC/MS: Rt=1.53 min. LC/MS (Condition A): 373.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].C([NH+](CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]3[NH:33][N:32]=[N:31][N:22]=3)=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=S(=O)(NCCc1ccc(Cc2nnn[nH]2)cc1)c1ccc(Cl)cc1

Procedure:
4.62 g. (13.8 mMol) 4-[2-(4-chlorobenzenesulphonamido)-ethyl]-phenylacetonitrile, 2.94 g. (21.3 mMol) triethylammonium chloride and 2.77 g. (42.6 mMol) sodium azide in 150 ml. 1-methylpyrrolidone are heated to 150° C. for 6 hours. The 1-methylpyrrolidone is subsequently distilled off in a high vacuum at 80° to 90° C., the residue is dissolved in dilute aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The aqueous phase is acidified with hydrochloric acid, also extracted three times with ethyl acetate, the extracts are dried over anhydrous sodium sulphate and, after treating with active charcoal, evaporated to dryness. The residue is taken up in an aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate and acidified, the product thereby crystallising out. There is obtained 1.5 g. (29% of theory) of the title compound in the form of colourless crystals; m.p. 168°-169° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[C:14]([O:18][C:19]([NH:21][OH:22])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:22][NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CC(=O)Oc1ccccc1C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino 2-(acetyloxy)benzoate is prepared from acetylsalicyloyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. 1H NMR (250 MHz, DMSO-d6) δ ppm 10.89 (1H, br. s.), 7.97 (1H, dd, 7.8, 1.7 Hz), 7.75 (1H, td, 7.8, 1.8 Hz), 7.46 (1H, td, 7.6, 1.1 Hz), 7.31 (1H, dd, 8.1, 0.9 Hz), 2.27 (3H, s), 1.42 (9H, s).