Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2.I[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu](I)I>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:16](=[O:21])[CH2:15][CH2:14]2
Reactant: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCC(=O)N2
Reactant: N#Cc1ccc(I)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCC(=O)N2c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A suspension of (2R)-6-[3-(2-methylpyrrolidin-1-yl)propoxy]-3,4-dihydroquinolin-2(1H)-one prepared in Example 1-(2) (0.20 g), 4-iodobenzonitrile (0.18 g), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.041 g), copper iodide (0.013 g) and cesium carbonate (0.45 g) in N,N-dimethylformamide (2 mL) was stirred at 100° C. for 16 hours. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (on a single plate of 2 mm thickness, developing solvent: chloroform/methanol=9/1) and NH-type preparative TLC (on two plates of 0.25 mm thickness, developing solvent: n-hexane/ethyl acetate=1/1) to give the titled compound (0.062 g, 23%) as a light-brown amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:19][C@@H:18]([NH:20]C(OC(C)(C)C)=O)[C:15]3([CH2:17][CH2:16]3)[CH2:14]2)[C:9]([CH3:28])=[C:8]2[C:3]=1[C:4](=[O:35])[C:5]([C:32]([OH:34])=[O:33])=[CH:6][N:7]2[CH:29]1[CH2:31][CH2:30]1.Cl.[OH-].[K+]>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:19][C@@H:18]([NH2:20])[C:15]3([CH2:16][CH2:17]3)[CH2:14]2)[C:9]([CH3:28])=[C:8]2[C:3]=1[C:4](=[O:35])[C:5]([C:32]([OH:34])=[O:33])=[CH:6][N:7]2[CH:29]1[CH2:31][CH2:30]1
Reactant: Cc1c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N2C[C@@H](N)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To 8.80 g of 5-amino-7-((S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 11 ml of hydrochloric acid was added and then stirred at room temperature for 1.5 hours. To the reaction mixture, a solution of 10.5 g of potassium hydroxide in 32 ml of water was added under ice cooling and resulting mixture was neutralized with 10% hydrochloric acid to pH 8. The deposited crystals were collected by filtration and washed with water. The crystals were diluted with methylene chloride, inorganic substance was filtered off and the resulting filtrate was evaporated. The residue was triturated with diethyl ether to give 5.53 g of the desired compound as yellow crystals. Recrystallization from acetonitrile gave yellow prisms, which was identified as the compound of Example 10.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[C:4]([CH:14]=[O:15])[CH:3]=1.[Cl:16]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[C:4]([CH:14]=[O:15])[C:3]=1[Cl:16]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Nc1cc(C=O)nc(C2CCCO2)c1F
Solvent: CC#N
Product: Nc1c(F)c(C2CCCO2)nc(C=O)c1Cl
Yield: 18.4 %

Procedure:
Using the procedure for Example 15, 4-amino-5-fluoro-6-(tetrahydrofuran-2-yl)picolinaldehyde (0.5 g, 2.379 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.258 g, 1.308 mmol) and CH3CN (24 mL) gave 4-amino-3-chloro-5-fluoro-6-(tetrahydrofuran-2-yl)picolinaldehyde (59 mg, 10.14%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 10.04 (m, 1H), 5.24 (td, J=7.0, 1.7 Hz, 1H), 4.86 (d, J=9.6 Hz, 2H), 4.11 (m, 1H), 3.98 (td, J=7.8, 5.6 Hz, 1H), 2.30 (m, 2H), 1.26 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −140.28; 13C NMR (101 MHz, CDCl3) δ 190.69, 148.31, 146.23, 145.56, 143.05, 139.88, 75.77, 69.34, 30.51, 26.31; EIMS m/z 243.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C:16]1([CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[N:33]=3)[N:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH4+:41]>CO.[NH4+].[OH-]>[NH2:41][CH:19]1[CH2:20][CH2:21][C:16]([CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[N:33]=3)[N:28]=[CH:27][CH:26]=2)([OH:15])[CH2:17][CH2:18]1
Reactant: [NH4+]
Reactant: COc1ccc2nccc(CCC3(O)CCC(=O)CC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nccc(CCC3(O)CCC(N)CC3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium triacetoxyborohydride (1.89 g, 8.75 mmol) was added to a solution of 4-hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanone (3 g, 8.5 mmol) and ammonium acetate (25.5 g) in methanol (65 ml). The reaction mixture was stirred at room temperature for 3 hours, 0.5 g of sodium triacetoxyborohydride was added and stirring was continued for a further 2 hours. The reaction mixture was diluted with NH4OH and extracted with EtOAc and dichloromethane. Organic phases were dried over MgSO4 and concentrated.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:6]2.[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]([F:15])([F:16])[F:14])[C:7]([C:17]([OH:19])=[O:18])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2cc(C(F)(F)F)ccc2NC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(C(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 25 °C

Procedure:
Ethyl 6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate from Step 3 (45 mg, 0.13 mmol) was suspended in methanol-tetrahydrofuran-water (10 mL, 7:2:1). Lithium hydroxide (24 mg, 0.52 mmol) was added, and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N HCl added until pH=1. The organic solvent was removed in vauco to afford a suspension of a crude yellow solid. Diethyl ether (20 mL) was added, and the solution was washed with water (2×20 mL), saturated ammonium sulfate (2×20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as a yellow solid, (0.041 g, 0.132 mmol, 99%): mp 150-156° C. 1H NMR (CD3OD/300 MHz) 7.78 (s, 1H), 7.48 (s, 1H), 7.40 (m, 1H), 6.81 (m, 1H), 5.17 (m, 1H). ESHRMS m/z 310.0307 (M−H, Calc'd 310.0303).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]32[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]3)=[CH:4][CH:3]=1.C[Si](N([Si](C)(C)C)C(=[O:27])C(F)(F)F)(C)C.BrBr>C(Cl)CCl>[OH:27][CH:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]2)[CH2:7]1
Reactant: O=C1NC(=O)C2(CCc3ccc(F)cc32)N1
Reactant: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: BrBr
Solvent: ClCCCl
Product: O=C1NC(=O)C2(CC(O)c3ccc(F)cc32)N1
Yield: 85 %

Procedure:
6'-Fluoro-spiro[imidazolidine-4,1'-indan]-2,5-dione, (C.A. reg. no. 66892-38-4)(1.1 g, 5 mmol) was combined with 2.65 ml (10 mmol) bis-(trimethylsilyl) trifluoroacetamide, 0.8 g (5 mmol) bromine and 30 ml ethylene dichloride and heated at reflux for 2.5 hours. During this time color was lost from the reaction mixture. The reaction mixture was concentrated in vacuo to an amber oil which was diluted with 10 ml water. Over a period of 16 hours at 25° C. a solid gradually formed. This material was isolated by filtration and dried in vacuo at 100° C. to give 1.0 g (85% yield) of the title compound: mp 209°-211° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C@H:11]1[O:13][CH2:12]1)[Cl:10]>>[CH2:1]([NH:8][CH2:12][C@H:11]([OH:13])[CH2:9][Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: ClC[C@@H]1CO1
Product: O[C@H](CCl)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.1 %

Procedure:
A scintillation vial was charged with benzylamine (1 g, 10 mmol), anhydrous petroleum ether (10 ml) and a stir bar. To this was added (S)-(+)-epichlorohydrin (0.925 g, 10 mmol) dropwise over a period of 20 min and the mixture was allowed to stir at room temperature. After 15 h, the white crystals precipitated from solution. These were collected by suction filtration, rinsed with cold petroleum ether (10 ml) and dried under vacuum to provide the title compound (1.0 g, 50%). Mass spectrum (ESI) 200.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]#[N:43])[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]#[N:43])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)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: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CCC#N)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (15 mg, 0.036 mmol; Peak 1, Example 49, Step 7), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (13 mg, 0.054 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 mg, 0.0018 mmol), and sodium bicarbonate (9.0 mg, 0.11 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol, purified with RP-HPLC (pH=10) to afford 12.1 mg of the desired product. LCMS (M+H)+: m/z=458.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:22]([OH:23])[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:22](=[O:23])[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccc3ccccc3c2C[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccc3ccccc3c2CC1=O
Temperature: 25 °C

Procedure:
Under argon to a solution of trans 2-tertbutoxycarbonylamino-1,2,3,4-tetrahydro-3-phenanthrenol (140 mg) in anhydrous methylene chloride (5 ml) was added Dess-Martin periodinane (281 mg). Agitation was maintained for 1 hour at room temperature and the reaction mixture was filtered on silica gel (30 g, elution with ethyl acetate:cyclohexane, 1:9). Evaporation of solvents gave the crude title compound (136 mg) which was recrystallized from a pentane/ethyl acetate mixture. The title compound was obtained as white needles (89 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH:15]=3)[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si]([N:32]=[C:33]=[N:34][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][C:17](=[N:34][C:33]#[N:32])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:20]4[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=4)[CH:15]=3)[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CC(=NC#N)c1cc(-c3cccc(C#N)c3)ccc1O2
Reaction time: 1 h

Procedure:
To a solution of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile (60 mg, 0.167 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.35 mL, 0.35 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.086 mL, 0.367 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (5 g), and stirred for 20 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(1′-acetyl-6-(3-cyanophenyl)spiro[chroman-2,4′-piperidine]-4-ylidene)cyanamide as light brown solid which was used for next step without further purification. MS ESI+ve m/z 385 (M+H)+.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[I-:17].[K+]>O.S(=O)(=O)(O)O>[I:17][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(F)c(F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a 1 liter four neck round bottom flask equipped with mechanical stirrer, two dropping funnels and a thermometer was introduced 20 g (86.71 mmol) of 2-amino-4,5-difluorobenzoic acid and a solution of 12.3 ml concentrated sulfuric acid in 90 ml water. The slurry was cooled to between 0° and -5° C. in an ice-acetone bath. One of the dropping funnels was charged with a solution of 6.57 g (95.22 mmol) sodium nitrite in 30 ml of water and slow addition of the solution was begun. The internal reaction temperature never rose above 0° C. and all the solution has been introduced after 5 minutes. The second dropping funnel was charged with a solution of 21.6 g (128.31 mmol) potassium iodide in 45 ml of 1N sulfuric acid. This solution was then added dropwise over a period of 10 minutes with the internal temperature at or below 0° C. During addition, the reaction mixture releases nitrogen gas which causes some foaming. Once the addition was completed, the dark mixture was stirred overnight while slowly warming to room temperature. The reaction mixture was quenched with a solution of 30 g of sodium bisulfite in 165 ml water and the suspension was adjusted to pH 2.5 with 5 ml of 6N hydrochloric acid. The resulting slurry was stirred at 0° C. for 30 minutes and then filtered. Purification of the dark material was effected by dissolving the majority of the solid in ethyl acetate followed by clarification and treatment with activated charcoal. After filtration through a filter aid (celite) and evaporation there was obtained 20 g (82%) of 2-iodo-4,5-difluorobenzoic acid; m.p.: 126°-127° C.
Reaction SMILES: [H-].[K+].[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=2)(=[O:5])[CH3:4].[CH3:32]OS(OC)(=O)=O.O>CS(C)=O>[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]1[N:20]([CH3:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=2)(=[O:5])[CH3:4]
Reactant: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3[nH]2)cc1OC
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3n2C)cc1OC
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
In dimethyl sulfoxide was slowly suspended 480 mg of 35% potassium hydride, and 1.37 g of 2-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-5,6-dimethoxyindole was added to the suspension, followed by stirring for 10 minutes. To the mixture was further added 700 mg of dimethylsulfate, followed by stirring for 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed successively with water and a saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Recrystallization of the residue from ethanol yielded 1.20 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:9](=[N:11]\O)/[CH3:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CN(C=O)C.CCOCC.[Fe].C[Si](Cl)(C)C>[F:1][C:2]1[C:3]([C:9]([NH:11][C:13](=[O:15])[CH3:14])=[CH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C/C(=N/O)c1ncc(F)cc1F
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(NC(C)=O)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
To a mixture of (Z)-1-(3,5-difluoropyridin-2-yl)ethanone oxime (Method 54, 12.5 g, 72.6 mmol), acetic anhydride (54.8 ml, 581 mmol), and iron powder (32.4 g, 581 mmol) in DMF (100 ml) was added TMSCl (0.01 ml, 0.073 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with ether (300 ml) and filtered through a short pad of celite. The filtrate was concentrated and the residue was partitioned between 200 ml of EtOAc and 50 ml of saturated sodium bicarbonate. The organic layer was separated and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc=2:1) to give the title compound as a white solid (2.70 g, 19%). 1H NMR (400 MHz) δ 9.55 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.97 (m, 1H), 5.87 (s, 1H), 5.14 (s, 1H), 1.99 (s, 3H). MS: Calcd.: 198. Found: [M+H]+ 199.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[CH:10]=[CH:9][C:8]=1[CH2:22][C:23](Cl)=[N:24][OH:25].[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[CH:10]=[CH:9][C:8]=1[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2F)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (2-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 96-1-4 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (32.0 mg, 23.9%).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>>[Cl:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(CC2CCCCC2)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(CC2CCCCC2)cnc1Cl
Temperature: 120 °C

Procedure:
A mixture of 1.8 g of 2-hydroxy-3-nitro-5-cyclohexylmethylpyridine (starting material E4) and 13 ml of phosphorous oxychloride is heated under reflux to 120° C. for two hours. After cooling the mixture is carefully added to ice/water, then neutralized with sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (ethylacetate/petroleum ether 1:15). Concentration of the chromatographically pure fractions gives 0.84 g of the title compound as an orange oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2=[O:20])=[CH:13][CH:12]=1.[NH4+].[Cl-].O>CCOCC.C1COCC1>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:20])=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)CC2

Procedure:
A solution of 3.0 M phenylmagnesium bromide in Et2O (680 mL, 2.04 mole) under argon at ambient temperature was diluted with Et2O (700 mL) with stirring, and a solution of 6-methoxy-1-indanone (277 g, 1.71 mole) in THF (1400 mL) was added dropwise over 1 hr. The reaction mixture was stirred for 2 h at ambient temperature and then was poured with stirring into saturated NH4Cl (2.8 L). H2O (1.4 L) was added, and the organic phase separated. The aqueous phase was extracted with Et2O (2×1 L), and the combined organic extracts were concentrated to give crude 6-methoxy-1-phenyl-1-indanol (445 g) as a brown oil. This oil was dissolved in toluene (2.5 L), and p-toluenesulfonic acid monohydrate (12.3 g, 0.065 mole) was added. The solution was stirred and heated at reflux for 16 hr using a Dean-Stark trap with a condenser. H2O collection was minimal after 2 h and totaled 28 mL. The solution was cooled and extracted sequentially with 5% aqueous Na2CO3 (1 L) and H2O (2×1 L). The organic layer was concentrated to give a dark brown oil (400 g). This oil was distilled under vacuum to give the title compound (298.2 g, 79%) as a yellow oil: bp 152-190° C./2.0 Torr; TLC (10% EtOAc/hexanes) Rf0.75.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[I-:32].[Li+].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([NH:43][CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46]O)[CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([NH:43][CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46][I:32])[CH:36]=1
Reactant: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Reactant: [I-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1NC(CCI)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of triphenylphosphine (1.83 g, 6.98 mmol) in dry tetrahydrofuran (30 ml) at 0° C. and under an atmosphere of nitrogen was added diethyl azodicarboxylate (1.2 g, 6.9 mmol) dropwise. After 20 minutes, lithium iodide and 4-chloro-2-[(3-hydroxy-1-phenylpropyl)amino]-benzonitrile (0.8 g, 2.79 mmol) were added to the mixture and stirring was continued for 5 h. The mixture was then concentrated to dryness, and the residue purified on silica (ether/isohexane 1:4). The title compound was isolated as a colourless solid (0.35 g, 32%).