Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=1)[CH3:11]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluorobenzonitrile (240 mg) and lithium carbonate (187 mg), the title compound was obtained as pale-yellow oil (yield: 188.6 mg, yield: 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH2:49]>CN(C=O)C>[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH:49][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
5-Fluoroindole-3-butyric acid (1.5 g, 6.8 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 8.2 mmole) and 1,3-diisopropylcarbodiimide (2.6 ml, 16.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.8 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions of the products were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3yl)-butanamide, as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].[H][H]>[Ni].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)C1(Cc2cccc(C#N)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1(Cc2cccc(CN)c2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of methyl N-tert-butoxycarbonyl-4-(3-cyano-benzyl)piperidine-4-carboxylate (0.6 g, 1.67 mmol), Raney nickel (3 g) in a mixture of ethanol (20 mL) and concentrated aqueous ammonium hydroxide (0.6 mL) was stirred under a balloon of hydrogen gas at room temp. overnight. The slurry was filtered, and the filtrate concentrated under vacuum to provide the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: N#CC1CN(CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol), 1-(3-chloropropyl)azetidine-3-carbonitrile (44.8 mg, 283 μmol, Eq: 3.0) and Cs2CO3 (123 mg, 377 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. LCMS showed complete reaction, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 68.9 μmol, 73.2%) as a white solid. MS (M+H)+=653.1; 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.36 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.56 (t, J=73.7 Hz, 1H), 5.75 (s, 2H), 4.57 (t, J=6.6 Hz, 2H), 3.24-3.40 (m, 3H), 2.50 (t, J=6.6 Hz, 2H), 2.08 (quin, J=6.5 Hz, 2H), 1.65 (s, 9H), 0.91-1.03 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([S:16][CH3:17])[C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Cl.[OH:19][NH2:20].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([S:16][CH3:17])[C:9](=[N:20][OH:19])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)C(SC)C2
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C)(C)C(=NO)C(SC)C2
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-3-methylsulfanyl-3,4-dihydro-1H-naphthalen-2-one (0.265 g, 1.05 mmol) in pyridine (5 ml) was added hydroxyamine hydrochloride (1.09 g, 15.7 mmol). The mixture was stirred under nitrogen at 85° C. overnight. The solution was cooled to room temperature, poured into water, extracted with ethylacetate, washed with 10% KHSO4 aqueous solution, brine, dried over MgSO4, filtered. The filtrate was evaporated under vacuo. The crude product was purified by flash column chromatography using ethylacetate:Hexane (1:9) as eluant to give the desired product as white solid (0.177 g, 63%). 1H NMR (CDCl3) δ: 8.80(br, 1H), 7.05(d, 1H, J=8.2 Hz), 6.93(d, 1H, J=2.5 Hz), 6.73(dd, 1H, J=8.2 and 2.5 Hz), 4.91(t, 1H, J=3.0 Hz), 3.81(s, 3H), 3.26(dd, 1H, J=15.6 and 5.0 Hz), 2.96(dd, 1H, J=15.6and 3.0 Hz), 2.15(s, 3H), 176(s, 3H), 1.48(s, 3H). 13C NMR (CDCl3) δ: 164.5, 159.1, 145.0, 129.6, 129.4, 111.8, 111.0, 55.3, 39.8, 35.9, 32.9, 32.4, 30.8, 15.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[F:12][C:13]1[C:14]([CH2:46]O)=[C:15]([F:45])[C:16]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C(C)(C)C)=[C:24]([F:35])[CH:23]=3)=[CH:19][C:18](=[O:36])[C:17]=2[C:37]=1[NH:38]C(=O)C(C)(C)C>>[NH2:38][C:37]1[C:17]2[C:18](=[O:36])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([F:35])[CH:23]=3)[O:21][C:16]=2[C:15]([F:45])=[C:14]([CH2:46][O:5][C:4](=[O:6])[CH2:3][CH2:2][Br:1])[C:13]=1[F:12]
Reactant: O=C(O)CCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCBr)c(F)c3o2)cc1F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
7.65 g (50.0 mmol) of 3-bromopropionic acid and 1.5 mL of sulfuric acid were added to 504 mg (1.00 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 118 (4), and the mixture was stirred at 100° C. for 10 minutes. The reaction solution was poured into 100 mL of ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=19:1), to give 163 mg of Compound 160 (yield: 35%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O[CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:40]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[C:16]4[N:10]([CH2:11][CH2:12][O:13][C:14]=3[CH:20]=2)[C:9]2[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:8]=2[C:7]=4[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(O)ccc1-3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc1-3
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.80 g, 2.04 mmol) in N,N-dimethylformamide (8 ml) were successively added tert-butyl 3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.09 g, 3.07 mmol) and potassium carbonate (0.57 g, 4.08 mmol) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give methyl 3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g). The obtained compound was used for Step 3 without purification.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C:33]([F:38])([F:37])[CH2:32]1>>[ClH:28].[F:37][C:33]1([F:38])[CH2:34][CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: FC1(F)CCCN(CCCl)C1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCCC(F)(F)C3)cc12

Procedure:
6-[2-(3,3-Difluoro-piperidin-1-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 67% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-3,3-difluoro-piperidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][C:12](=[O:14])[NH:13][C:15]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Yield: 44.7 %

Procedure:
A mixture of N-(tert-butoxy carbonyl)-L-glutamine (4.92 g, 20 mmol) and carbonyl diimidazole (3.24 g, 20 mmol) in THF (100 mL) was refluxed for 16 h. Thereafter, solvent was removed and the crude product was recrystallized from hot EtOAc to give compound 203 (2.04 g, 45%) as white crystals: mp 214-215° C.; 1H NMR (DMSO-d6) δ 4.22 (dd, J=6.2 Hz, J=11.0 Hz, 1H), 2.77-2.65 (m, 1H), 2.45 (m, 1H), 1.96-1.87 (m, 2H), 1.40 (s, 9H); MS (CI/CH4) m/z 227 [M-1]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[F:29][C:30]1[C:31]([N+:41]([O-:43])=[O:42])=[C:32]([CH:37]=[C:38](F)[CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].C([O-])([O-])=O.[Na+].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:24]([C:38]3[CH:39]=[C:30]([F:29])[C:31]([N+:41]([O-:43])=[O:42])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.850 g, 4.60 mmol), methyl 3,5-difluoro-2-nitrobenzoate (1.996 g, 9.19 mmol) and Na2CO3 (1.462 g, 13.79 mmol) in hexamethylphosphoramide (25 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and filtered through a pad of Celite®. The filtrate was washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (0-35% EtOAc in hexanes) to give methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate (1.61 g, 58% yield) as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.62 (br. s., 1H), 0.79-0.95 (m, 2H), 0.96-1.11 (m, 1H), 1.84-1.97 (m, 1H), 3.01 (d, J=5.0 Hz, 3H), 3.31-3.36 (m, 3H), 3.87 (s, 3H), 5.82 (d, J=4.6 Hz, 1H), 7.22 (t, J=8.6 Hz, 2H), 7.37-7.44 (m, 1H), 7.50-7.54 (m, 2H), 7.56 (s, 1H), 7.83-7.92 (m, 2H). LCMS (m/z, ES+)=600.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:20]3[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)[CH2:32][CH2:33][CH3:34])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCCI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1nc(Cl)ncc1C
Reaction time: 0.5 h
Yield: 361.4 %

Procedure:
To a solution of ethyl((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 408, 800 mg, 0.25 mmol) in DMF (20 mL) was added portion wise NaH (118 mg, 2.97 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodopropane (0.39 mL, 3.96 mmol) was added. After 18 h of stirring at rt, the excess NaH was quenched by the slow addition of brine (40 mL) [H2 evolution]. The product was then extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (403 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H), 1.30 (t, 3H), 1.65 (t, 2H), 1.74-1.79 (m, 1H), 2.06-2.11 (m, 2H) 2.27 (s, 3H), 2.37-2.45 (m, 2H), 2.70-2.74 (dd, 1H), 2.84-2.91 (m, 2H), 3.45-3.55 (m, 3H), 3.73 (t, 2H), 3.97 (t, 2H), 4.16 (q, 2H), 6.68 (d, 1H), 6.6.74 (s, 1H), 7.05 (d, 1H), 7.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[C:16]([Cl:29])[C:15]=1[O:30][CH3:31].CN1C=CN=C1>[Cl-].[Cl-].[Zn+2].C(O)(C)(C)C.ClCCCl>[Cl:29][C:16]1[C:15]([O:30][CH3:31])=[C:14]([NH:13][C:2]2[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH:28]=[CH:27][C:17]=1[CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1Cl)OCC
Agent: Cn1ccnc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1Cl)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (2.1 g, 9.77 mmol) in a 1:1 mixture of DCE and t-butanol (20 mL) was added ZnCl2 (1M, 10 mL) and stirred for half an hour at RT. After cooling at 0° C. diethyl 4-amino-2-chloro-3-methoxybenzylphosphonate (3 g, 9.77 mmol) in a 1:1 mixture of DCE and t-butanol (20 mL) was added followed by N-methylimidazole (800 mg, 9.75 mmol) drop wise while stirring was continued for 24 hrs. The solvents were removed under reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate and hexanes (1:1)) to yield the desired compound in 1.5 g (32%) yield. 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.38 (d, 1H), 8.03 (s, 1H), 4.01-4.18 (q, 4H), 3.98 (s, 3H), 3.29 (d, 2H), 1.24 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O>[N:11]([CH2:4][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[N+:12]=[N-:13]
Reactant: Fc1cccc(F)c1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c(F)cccc1F

Procedure:
2,6-difluorobenzylchloride of formula II and sodium azide are reacted in the presence of DMSO to obtain 2-(azidomethyl)-1,3-difluorobenzene of formula III, which is then treated with 2-propiolic acid to give a carboxylic acid intermediate which on further reaction with methanol in the presence of sulfuric acid yields methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate intermediate of formula IV. This intermediate is then isolated and further reacted with methanolic ammonia to yield rufinamide of formula I.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:22](=[O:23])[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)Oc1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 35 using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and phenyl chloroformate as the starting materials. LCMS for C17H10BrFN5O5 (M+H)+: m/z=461.9, 463.7.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH:19]=[CH2:20])[O:13][CH2:14][CH:15]=[CH2:16])[P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].C(Cl)Cl.C[N:28](C=O)C>C1COCC1>[NH2:28][CH:1]([P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6])[P:12](=[O:21])([O:13][CH2:14][CH:15]=[CH2:16])[O:17][CH2:18][CH:19]=[CH2:20]
Reactant: CN(C)C=O
Reactant: C=CCOP(=O)(CP(=O)(OCC=C)OCC=C)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)C(N)P(=O)(OCC=C)OCC=C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of bisphosphonate 23 (2.0 g, 5.95 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 254 mg, 6.35 mmol) portionwise. The solution was stirred for 45 min at room temperature and added to a solution of O-(diphenylphophinyl)hydroxylamine (1.35 g, 5.77 mmol) in THF (40 mL), cooled in a dry ice/acetone bath. The resulting mixture was stirred for 10 min at the same temperature then 18 h at room temperature. CH2Cl2 (40 mL) was added, the solids were removed by filtration and washed with several portions of CH2Cl2. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 0-5% MeOH/EtOAc to provide aminobisphosphonate 24 as a clear yellow oil (1.24 g, 3.53 mmol, 59%). 1H NMR (400 MHz, CDCl3) δ 1.69 (bs, 2H), 3.52 (t, J=20.8 Hz, 1H), 4.64-4.67 (m, 8H), 5.24-5.27 (m, 4H), 5.36-5.42 (m, 4H), 5.92-6.02 (m, 4H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][CH:8]([F:28])[O:9][C:10]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>C(#N)C.O>[F:28][CH:8]([F:7])[O:9][C:10]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:11]=1[C:12]([NH:14][CH3:1])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(C(N)=O)c2)OC1(C)C
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine) palladium0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH2Cl2 and extracted with CH2Cl2. Combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC(N(C)C)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH:26]=O.OS([O-])=O.[Na+]>O>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[C:26]([C:25]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=1)[N:6]=[C:4]2[OH:5]
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(O)c2cc1OC
Temperature: 139 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 2-amino-4,5-dimethoxybenzamide (12 g, 61.16 mmol, 1.00 equiv), dimethylacetamide (200 mL), 3,4,5-trimethoxybenzaldehyde (12 g, 61.16 mmol, 1.00 equiv) and NaHSO3 (9.55 g, 91.83 mmol, 1.50 equiv). The resulting solution was stirred overnight at 139° C. The mixture was cooled to room temperature. The resulting solution was diluted with 800 mL of water. The solids were collected by filtration. The filter cake was washed with 1×100 ml of water, 100 ml of diethyl ether and 100 mL of methanol. This resulted in 12 g (53%) of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a brown solid. MS (ESI) m/z 373 [M+h]+