Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[F:10]F>O>[F:10][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: FF
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1F
Reaction time: 48 h

Procedure:
The preceding example was substantially repeated but at a lower reaction temperature. A suspension of 6-methyl uracil (4.00g) in water (30 ml) was maintained at 0°-10°C and fluorinated with a stream of fluorine and nitrogen, present in equal volumes, until fluorine was detected at the reactor outlet. The reaction mixture was allowed to stand for two days at room temperature and 1.05g of crystals were collected and found to have a different IR spectrum than the starting material. A DSC analysis showed 2 transitions at 313°C and 318°C followed by apparent decomposition. The structure of the product was identified as 5-fluoro-6-methyl uracil by NMR analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:12][C:13](=[O:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (132 mg, 0.295 mmol) ures similar to those in Example 1, was dissolved in dichloromethane (8 mL) and cooled to 0° C. Dess-Martin periodinane (187 mg, 0.441 mmol) was added and the mixture was stirred at ambient for 2 h. The mixture was quenched with saturated sodium bicarbonate solution: 10% sodium thiosulfate solution (1:1; 6 mL) and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 40-50% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (122 mg, 0.273 mmol, 93% yield): 1H NMR (400 MHz, CDCl3): 8.43 (br s, 1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.20 (m, 1H), 6.86 (ddd, 1H), 6.64 (ddd, 1H), 4.94-4.93 (m, 4H); MS (EI) for C16H10F3IN2O2: 447 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1.CO.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1
Reactant: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Reactant: CN
Solvent: CO
Product: CNc1ccc2nc(-c3cccc(C#N)c3)cn2n1
Temperature: 125 °C

Procedure:
A mixture of 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (0.25 mmol) and 10 mL methylamine methanol solution was heated at 125° C. in microwave synthesizer for 30 min. After purification to provide 3-(6-(methylamino)imidazo[1,2-b]pyridazin-2-yl)benzonitrile.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl-].C[Al+]C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:19](OC)=[O:20])=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:19](=[O:20])[CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)c1cccc(F)c1
Reactant: CNOC
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)C(Cc1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension N-methoxy-N-methylamine hydrochloride (2.0 g, 21 mmol) in 50 mL CH2Cl2 at 0° C. was added dimethylaluminum chloride (1 M in hexane, 21 mL, 21 mmol). After stirring at room temperature for 1 h, a solution of methyl 3-(4-chlorophenyl)-2-(3-fluorophenyl)propionate (Step A, 2.0 g, 10 mmol) in CH2Cl2 (10 mL) was added, and the resulting mixture was stirred overnight. The reaction mixture was quenched by addition of MeOH (5 mL), and the resulting mixture was concentrated with silica gel (50 g). The material was loaded onto a silica gel column, which was eluted with 10% EtOAc in hexane to 2% ammonia in MeOH (2 M) in 10% EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.35-6.90 (m, 8H), 4.39 (br, 1H), 3.41 (s, 3H), 3.38-3.30 (m, 1H), 3.08 (s, 3H), 2.92 (dd, 1H). LC-MS: m/e 322 (M+H)+ (3.6 min).
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:24]\[OH:25])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccncc1-c1ccnc(C(=O)c2ccccc2)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccncc1-c1ccnc(/C(=N\O)c2ccccc2)c1F
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A solution of (3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(phenyl)methanone (0.025 g, 0.086 mmol) and hydroxylamine hydrochloride (0.040 g, 0.582 mmol) in pyridine (Volume: 0.428 ml) was refluxed for 2.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 80-100% EtOAc in hexanes over 10 min, tr=0.3, 1.5, 2 min) gave the title compound (23.7 mg, 0.076 mmol, 89% yield) as a yellow residue. ESI MS (M+H)+=308.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9](I)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[Li]CCCC.CN([CH:22]=[O:23])C>O1CCCC1>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:22]=[O:23])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCc1cc(C)c(I)cc1C(=O)O
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C)c(C=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a stirred solution of 2-ethyl-5-iodo-4-methylbenzoic acid (compound 211.3, 5.00 g, 17.2 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) at −78° C. under nitrogen was added dropwise n-BuLi (17 mL, 2 M in THF, 2.00 equiv). After 1 h at −78° C., DMF (7.00 g, 95.8 mmol, 3.00 equiv) was added dropwise at −78° C. The resulting solution was slowly warmed up to 25° C., then carefully quenched with water followed by the addition of 10 mL of HCl (aq., 6 M). The aqueous phase was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (2:1) as eluent to furnish 450 mg (14%) of 2-ethyl-5-formyl-4-methylbenzoic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[NH2:6][C:4]([C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: Cc1cccc(N)c1C(N)=O
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccc(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 2-amino-6-methylbenzamide (1.28 g, 8.52 mmol) and triethylamine (1.03 g, 10.2 mmol) in THF (30 mL) was added dropwise ethyl chloroglyoxylate (1.28 g, 9.38 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether-ethanol, and the insoluble material was collected by filtration to give ethyl ((2-(aminocarbonyl)-3-methylphenyl)amino)(oxo)acetate as a white powder (1.85 g, 87%).
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:27][C:19]2=[N:20][C:21]([CH3:26])=[CH:22][C:23]([O:24][CH3:25])=[C:18]2[C:17]=1[OH:28])=O)C>>[CH3:25][O:24][C:23]1[CH:22]=[C:21]([CH3:26])[N:20]=[C:19]2[O:27][CH2:16][C:17](=[O:28])[C:18]=12
Reactant: CCOC(=O)c1oc2nc(C)cc(OC)c2c1O
Agent: O=C1COc2cnccc21
Product: COc1cc(C)nc2c1C(=O)CO2

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-4-methoxy-6-methylfuro[2,3-b]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:32][C:31]=3[O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:27][NH:28][CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:32][C:31]=3[O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:27][N:28]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
Para toluene sulphonyl chloride (180 mg, )0.95 mmol) was added to a stirred solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.9 mmol) in dichloromethane (10 ml) and pyridine (0.9 mmol). Stirring was continued for 18 h, then the solution was partitioned between water (20 ml) and ethyl acetate (2×20 ml). The combined organic phases were dried over magnesium sulphate, and concentrated in vacuo to leave a yellow oil. Purfication on silica (20 g) eluting with hexane, followed by hexane:diethyl ether, 1:1, then diethyl ether gave 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (490 mg, 77%)
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15][C:14](=[O:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].OO.[Na+].[Cl-]>C1COCC1>[Si:1]([O:8][C@@H:9]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:47])[F:49])[CH:41]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH2:15][C@H:14]([OH:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](COc1cccc(C(F)(F)F)c1)O[Si](C)(C)C(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Reaction time: 1 h
Yield: 33 %

Procedure:
To a cold solution of crude compound (10a) (155 g) prepared in EXAMPLE 16 in THF (450 mL) was added a solution of L-Selectride in THF (1.06 M, 230 mL). 30% H2O2 (40 mL) was then added at −30° C., stirred for 1 h. Saturated aqueous NaCl (150 mL) was added into the reaction mixture, the layers were separated, the aqueous layer was extracted twice with MTBE or toluene (PhMe) (300 mL each) and then the combined organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography to furnish 51.3 g of compound (11a) (92% HPLC purity, 50% yield). This was used directly in EXAMPLE 18.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16]CC)=[O:15])[CH:11]([CH3:19])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH:11]([CH3:19])[CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Agent: Cl
Solvent: C1COCCO1
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)O
Temperature: 60 °C
Yield: 98.3 %

Procedure:
Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (3.65 g, 10.38 mmol) was dissolved in a mixture of HCl (6 N aqueous, 20 mL) and 1,4-dioxane (50 mL) and the resulting mixture was heated at about 60° C. for about 72 h. The organic solvent was removed under reduced pressure. The aqueous phase was neutralized by the addition of saturated aqueous NaHCO3 (40 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (40 mL), dried over anhydrous MgSO4 and concd under reduced pressure to yield 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%) as a white amorphous solid: LC/MS (Table 1, Method a) Rt=1.66 min; MS m/z 324 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([C:13]2[CH:14]=[CH:15][O:11][CH:12]=2)[CH:9]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: OB(O)c1ccoc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: N#Cc1ccc(F)cc1-c1ccoc1
Yield: 32 %

Procedure:
Following the same procedure used for AUP01158-1, AUP01162-1 was prepared from 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol), furan-3-ylboronic acid (3.36 g, 30.0), Pd2(dba)3 (100 mg), 1,2-dimethoxyethane (25 mL) and 2M Na2CO3 (40 mL). The crude was purified by Combi flash chromatography (24 g column, 8 g silica, gradient of eluent from PE to PE/EtOac 9/1) to give the title compound as a light yellow solid. This solid had to be purified an ultimate time by drying under vacuum at 60° C. for 3 days. Finally, pure expected compound was obtained as an off white solid in 32% yield (1.47 g); mp 42-68° C. (dec.); 1H NMR (270 MHz, CDCl3) δ 6.81 (1H, d, J=2.0 Hz, ArH), 7.07 (1H, td, J=2.5 and 8.0 Hz, ArH), 7.24 (1H, dd, J=2.5 and 8.7 Hz, ArH), 7.52-7.55 (1H, m, Add), 7.72 (1H, dd, J=5.8 and 8.7 Hz, ArH), 8.06 (1H, s, ArH); HRMS (ESI) calcd. for C11H7FNO (M+H)+188.0506. found 188.0513.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.[H-].[Na+].Br.Br[CH2:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.BrCC1C(O)=CC=CN=1>CN(C=O)C>[OH:21][C:20]1[C:15]([CH2:14][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1cc[nH]n1
Reactant: Oc1cccnc1CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
Intermediate 1 (200 mg, 1.598 mmol) was dissolved in 2 mL of anhydrous DMF at 0° C. Sodium hydride (ALDRICH, 48.5 mg, 1.920 mmol) was added and mixture of reaction was stirred at 0° C. for 20 minutes. 2-(Bromomethyl)-3-pyridinol hydrobromide (ALFAAESAR, 301 mg, 1.598 mmol) was dissolved in 2 mL of DMF (anh) at 0° C. Sodium hydride (ALDRICH, 48.5 mg, 1.920 mmol) was added and this solution was stirred at 0° C. for 20 minutes. Solution of 2-(bromomethyl)-3-pyridinol was added dropwise to reaction mixture. Reaction was stirred at 80° C. for 24 h. Solvent was evaporated to dryness. Residue was partitioned between EtOAc and NH4CI. Organic layer was dried over MgSO4 (anh), filtered and concentrated to dryness. Residue was purified using silica chromatography column using a linear gradient of DCM/MeOH as eluents to give the title compound (48.5 mg, 0.207 mmol, 13% yield). 1H NMR (300 MHz, CDCl3) δ ppm: 9.70 (br s, 1H), 8.04 (m, 1H), 7.46 (d, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.53 (d, 1H), 5.42 (s, 2H), 2.27 (s, 3H). [ES+MS] m/z 233 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(Br)nc1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 5.058 g of 3,5-dibromo-pyrazin-2-ylamine in 100.0 ml 1,2-dimethoxyethane was added at room temperature 1.156 g of tetrakis(triphenylphosphine) palladium (0) and stirred for 0.5 hours. To the resulting mixture was added a solution of 5.30 g sodium carbonate in 50.0 ml water and 3.078 g 4-fluorophenylboronic acid. The mixture was heated to 100° C. for 5 h. The resulting yellow solution was partitioned between 10% aqueous citric acid and ethyl acetate. The organic layer washed with 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of heptane to dichloromethane to yield 3.22 g of the title compound as white crystals. MS (ISP) (M+H+)=268.1 and 270.1
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:23])[CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[H-].[Na+]>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([O:23][CH3:1])[CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(c1ccc(Cl)c(Cl)c1)C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
Methyl iodide (0.1 mL, 1.20 mmol) was slowly added to 15 mL of tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (200 mg, 0.602 mmol) and NaH (44 mg, 1.20 mmol) dissolved in a distilled methylene chloride solution at 0° C., and the mixture was stirred for 4 hours. Thereafter, purified water (3 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with methylene chloride (3*30 mL), and the organic layer was washed with a saturated sodium chloride solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain a colorless liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (4:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (4:1, v/v)).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:18]#[CH:19].[C-]#[C-].[Na+].[Na+]>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)([OH:7])[C:18]#[CH:19])=[CH:4][CH:3]=1
Reactant: C#C
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: [C-]#[C-]
Agent: [Na+]
Product: C#CC(O)(c1ccc(F)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro-4′-methoxy-benzophenone from Step 1 (126.7 grams) and acetylene saturated N,N-dimethylformamide (380 mL) were combined in a reaction flask. Sodium acetylide solution (9 weight % in toluene, 343 grams) was added to the reaction mixture dropwise over 45 minutes. The reaction mixture was stirred at room temperature for 1 hour and then poured into ice water (600 mL). The layers were phase separated and the aqueous layer was extracted with three portions of diethyl ether (200 mL). The organic layers were combined and washed with saturated aqueous NH4Cl (200 mL), saturated aqueous NaCl (200 mL), and saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to an amber colored oil yielding 136.6 grams of 1-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol. This material was not purified further but was used directly in the next step.
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[O:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenoxymethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.545 mmol) described in Manufacturing Example 86-1-5 and 3-ethynyl-pyridin-2-ylamine (41 mg, 0.348 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (104 μL, 0.747 mmol), which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and 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 (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (39 mg, 20%).