Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]4)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc2cc(N)ccc2n1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc2cc(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc2n1

Procedure:
The title compound was prepared from 45C by procedures analogous to those described in Experiment 2E and 2F. HPLC: 100% at 1.81 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19](=O)[CH:20]([CH3:22])[CH3:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[OH:18])=[O:10])=[CH:4][CH:3]=1.Cl.[OH-].[NH4+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:18][C:19]=2[CH:20]([CH3:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C(C(=O)c1ccc(F)cc1O)c1ccc(Cl)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1oc2cc(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(4-fluoro-2-hydroxy-phenyl)-4-methyl-pentane-1,3-dione (16.4 g, 49 mmol) in glacial acetic acid (150 ml) is added concentrated HCl (20 ml). The reaction mixture is stirred at 140° C. for 2 h, allowed to cool and then poured into a mixture of 880 ml of ammonium hydroxide and ice (200 ml). Ethyl acetate (300 ml) is added with vigorous stirring. The phases are separated, and the aqueous phase is washed with ethyl acetate (200 ml). The organic phases are combined, washed with water and brine and dried (MgSO4). The solvent is removed in vacuo, and the crude product is purified by flash chromatography on silica gel using iso-hexane:ethyl acetate (25:1 to 15:1) as the eluent. The resulting oil is crystallised from iso-hexane (150 ml) to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][NH:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)CCCC(C)(C)N1.Cl[C:30]1([C:36]([O:38][CH3:39])=[O:37])[C:34](=[O:35])[CH:33]=[CH:32][S:31]1>ClCCl.C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:32]3[S:31][C:30]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([OH:35])[CH:33]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2[nH]cnc2cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reaction time: 12 h

Procedure:
To a mixture of 21.2 g of 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridine and 11.36 g of 2,2,6,6-tetramethylpiperidine in 2 l dichloromethane was slowly added a solution of 8.77 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 300 ml chloroform at 30-40° C. The reaction mixture was stirred for 12 h, washed with water (2×200 ml) and concentrated under vacuum. The residue was purified by flash chromatography (eluents: ethyl acetate/methanol/triethylamine) two times and after precipitation from ethyl acetate/n-hexane the title compounds were obtained as a mixture of regioisomers.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: COc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, aluminum chloride (1.95 g, 14.6 mmol) is slurried in dichloromethane (50 mL) then 4-chloro-3-sulfamoyl benzoyl chloride is added and allowed to stir at ambient temperature for 30 minutes. Anisole (683 mg, 6.3 mmol) is added in 2 mL methylene chloride. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a colorless oil. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded a white foam which is crystallized three times from ether to afford the title compound. 1H NMR (MeOD) δ 3.9 (s, 3H), 7.1 (d, 2H, J=8.84 Hz), 7.7-8.0 (m, 4H), 8.4 (d, 1H, J=1.96 Hz). MS (m/z): 326 (M+1). CHN Calc C, 51.62; H, 3.71; N, 4.3. Found C, 51.70; H, 3.76; N, 4.22. M.P. 156-158° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:16]3=[O:37])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17][C:16]3=[O:37]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1cc(O)ccc12
Yield: 82.3 %

Procedure:
A suspension of 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.60 g, 1.2 mmol) in methanol (20 mL) was degassed by bubbling through nitrogen for 1 h before palladium hydroxide on carbon (20%, 0.08 g, 0.12 mmol) was added. The mixture was stirred under 120 psi hydrogen at 60° C. for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue obtained was recrystallized from ethyl acetate and hexanes to afford 6-hydroxy-2H-spiro[benzofuran-3,3′-indolin]-2′-one (0.25 g, 83%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 10.86-9.35 (br, 2H), 7.19 (td, J=7.6, 1.2 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.96-6.84 (m, 2H), 6.42 (d, J=8.2 Hz, 1H), 6.29 (d, J=2.1 Hz, 1H), 6.17 (dd, J=8.2, 2.1 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 4.59 (d, J=9.2 Hz, 1H); MS (ES+) m/z 254.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.CN(C)CCN(C)C.C([Li])CCC.[I:26]CI>O.C(OCC)C>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[C:7]([I:26])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2ccccc21
Reactant: ICI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCOc2c(I)cccc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2.00 g (12.3 mmol) of 4,4-dimethylchroman and 30 ml of ethyl ether are introduced into a three-necked flask under argon. 2.4 ml (15.9 mmol) of tetramethylethylenediamine (TMEDA) are added dropwise, the mixture is cooled to −78° C. and 5.9 ml (14.8 mmol) of n-butyllithium (2.5M in hexane) are added dropwise. The temperature is allowed to return to −20° C. over two hours and then to room temperature and the mixture is stirred for 12 hours. 1.3 ml (16.0 mmol) of diiodomethane and 15 ml of ethyl ether are introduced into another three-necked flask under argon. Cooling is carried out to 0° C. and the preceding solution, cooled beforehand to −78° C., is introduced, then the reaction mixture is allowed to return to room temperature and stirred for 12 hours. The reaction mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, 1.30 g (37%) of the expected compound are collected in the form of a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:15][C:13]1[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 0.73 mmol) from Example 51, Step A in DMF (3 mL) was added 3,4-difluorobenzyl bromide (0.122 mL, 0.95 mmol) and then cesium carbonate (310 mg, 0.95 mmol). The reaction was stirred at 50° C. for 3 h and was then diluted with water and extracted three times with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude products. The products were separated by preparative TLC (3×1 mm) eluted with 25% ethyl acetate in hexanes to yield faster eluting O-alkylation title product. HPLC/MS: 534 (M+1), 536 (M+3); Rt=5.17 min. 1HNMR (CDCl3): δ 3.981 (s, 3H), 5.489 (s, 2H), 7.04 (br d, J=8.4 Hz, 2H), 7.11 (d, J=8.2 Hz, 1H), 7.2-7.6 (m, 3H), 7.38 (d, J=2.0 Hz, 1H), 8.285 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:17]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:45]([O:44][C:42]([N:36]1[CH2:41][CH2:40][N:39]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:35])[CH2:38][CH2:37]1)=[O:43])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 3.5 g (S)-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-pentanedioic acid 5-tert-butyl ester in 11 ml DMF were added 1.36 ml benzyl 1-piperazinecarboxylate, 3.61 ml N-ethylmorpholine and 2.3 g TOTU. After 2 h the reaction mixture was diluted with ethyl acetate and extracted with aqueous NaHCO3 and aqueous LiCl (4% w/w). The crude product product obtained after evaporation of the solvent (4.4 g) was used in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (3) (923 mg, 2.99 mmol) and 2-methylpropane-2-sulfinamide (1.450 g, 11.96 mmol, 4 eq.) in anhydrous THF (75 mL) was added Ti(OEt)4 (5.46 g, 4.96 mL, 23.92 mmol, 8.0 eq). The resulting mixture was heated to reflux overnight. LC-MS showed ca. 45% conversion. After another 8 h, no further improvement. To the refluxing mixture was added 2-methylpropane-2-sulfinamide (0.725 g, 5.98 mmol, 2 eq.) and Ti(OEt)4 (2.73 g, 2.5 mL, 11.96 mmol, 4.0 eq) and followed by another equal portions of 2-methylpropane-2-sulfinamide and Ti(OEt)4 after 14 hours. The reaction mixture was refluxed for another 2 days, 93% conversion achieved at this point. The reaction was quenched with brine (3 mL) after cooled down to room temperature. The mixture was stirred for another 30 min before filtered through a short pad of Celite®. The filter cake was washed with EA, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography. The fraction of desired product with 2-methylpropane-2-sulfinamide was dissolved in EA (100 mL) and washed with saturated aqueous NaHCO3 (45 mL), 1 M NaOH (40 mL) and brine successively. Solvent was removed under reduced pressure after dried over Na2SO4 and filtered to afford 0.968 g of the desired product 4 as a light yellow solid. MS ESI+ve m/z 412 (M+H)30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@@H:5]1[O:7][CH2:6]1)[CH3:2].[Cl-].[NH4+].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([OH:7])[CH2:6][N:11]=[N+:12]=[N-:13])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CN=[N+]=[N-]
Temperature: 75 °C
Yield: 69.1 %

Procedure:
Ethyl-(2R)-2,3-epoxyproprionate (0.5 g, 4.3 mmol), ammonium chloride (0.253 g, 4.73 mmol), and sodium azide (0.336 g, 5.17 mmol) were combined in DMF (8 mL), and the mixture was heated at 75° C. for 14 hours. The reaction was cooled to room temperature, and was partitioned between water and ether/hexanes (1:1 v/v). The phases were separated, and the organic phase was washed once each with water, brine, dried over MgSO4, filtered, and concentrated to an oil, which was purified by flash chromatography (silica gel/hexanes: 10% ethyl acetate) to give (R)-ethyl-3-azido-2-hydroxypropionate as a clear oil (0.47 g, 2.97 mmol, 69% yield). Rf 0.27 (hexanes: 10% EtOAc, v/v, p-anisaldehyde); MS m/e [M+Na]+ calcd 182.1, found 182.0.
Reaction SMILES: [S:1]1[C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:7][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[N:8][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N=C(N)c1cc2ccccc2s1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cc3ccccc3s2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=400.9 (M+H+), was prepared from benzo[b]thiophene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([O-])[CH:4]=[C:3]([CH2:8][C:9]#[N:10])[CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:3]([CH2:8][C:9]#[N:10])=[CH:2][CH:1]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CCc1ccc[n+]([O-])c1
Product: N#CCc1cccnc1Cl
Temperature: 5 °C
Yield: 42.9 %

Procedure:
(1-oxypyridin-3-yl)acetonitrile (7.5 g, 35.9 mmol) is carefully added to vigorously stirred phosphorous oxychloride (100 mL). The mixture is slowly heated to 80° C. (in 5° C. increments) over 1.5 hr. (CAUTION. If heating is too quick, violent decomposition occurs at ca 70° C.) All the solids dissolved. The reaction is heated at reflux for 3 hr. The excess phosphorous oxychloride is removed and the residue is cautiously treated with cold water. Saturated sodium bicarbonate is added to make the mixture basic, then it is extracted with ethyl acetate (3×). The combined extract is washed with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-10 to 100% ether. The second compound off the column is the desired (2-chloropyridin-3-yl)acetonitrile (2.35 g, 42.9% yield) a light brown solid.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH:36]([O:39][C:40]([N:42]1[C:51]2[C:46](=[N:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[C@H:45]([N:54]([CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:73])[F:72])[CH:62]=2)[C:55]2[N:56]=[N:57][NH:58][N:59]=2)[CH2:44][C@@H:43]1[CH2:75][CH3:76])=[O:41])([CH3:38])[CH3:37]>ClCCl>[CH:36]([O:39][C:40]([N:42]1[C:51]2[C:46](=[N:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[C@H:45]([N:54]([CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:68])([F:69])[F:70])[CH:64]=[C:63]([C:71]([F:72])([F:73])[F:74])[CH:62]=2)[C:55]2[N:56]=[N:57][N:58]([CH3:1])[N:59]=2)[CH2:44][C@@H:43]1[CH2:75][CH3:76])=[O:41])([CH3:38])[CH3:37]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
Add triphenylphosphine (27 mg, 0.104 mmol), methanol (17 mg, 0.52 mmol), and diisopropylazodicarboxylate (0.018 mL, 0.104 mmol) to a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester in dry dichloromethane (1 mL) and stir the mixture for 15 h at room temperature. Remove the solvent in vacuo and purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford the title compound (41 mg, 66%). MS (ES+): 602 (M+H).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=[C:34]1[CH2:33][CH2:32][CH2:31]CC2.BrCC1CC1>C(O)C>[CH:33]1([CH2:34][O:26][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]4[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:27])[CH2:31][CH2:32]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: BrCC1CC1
Solvent: CCO
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC3CC3)c2)n1

Procedure:
0.12 g of N-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 97 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of ethanol. 0.15 ml of (bromomethyl)cyclopropane was added thereto and refluxed with heating for 3 hours. The solvent was distilled off, and water was added to the residue. Ethyl acetate extraction was performed. The organic layer was washed twice with water, and concentrated. The residue was purified by silica gel column choromatography (n-hexane:ethyl acetate=1:1). The obtained crude crystals were recrystallized using an ethanol-n-hexane mixture, and 60 mg of white powdery N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:18]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[N:25]=[CH:26][C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Yield: 58 %

Procedure:
Methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (875 mg, 3.68 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.06 g, 4.41 mmol), caesium carbonate (3.59 g, 11.03 mmol), and bromotris(triphenylphosphine)copper (0.69 g, 0.735 mmol) were added together in DMA (16 mL) and heated in a microwave reactor at 160° C. for 9 hours. The mixture was taken up in water (25 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (5×30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated to give a brown solid which was triturated with diethyl ether to give the desired compound as a beige solid (820 mg).
Reaction SMILES: C(O)(=O)C#CC.[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:45])=[C:33]([NH:35][C:36]([C:38]4[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=4)=[O:37])[CH:34]=3)=[N:24][N:23]2[CH:46]=1>CN(C)C=O.CN(C)C(=O)C>[C:11]([NH:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:45])=[C:33]([NH:35][C:36]([C:38]4[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=4)=[O:37])[CH:34]=3)=[N:24][N:23]2[CH:46]=1)(=[O:7])[C:10]#[C:9][CH3:8]
Reactant: C1CCOC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: CC#CC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 37 %

Procedure:
In the same manner as in Example 279 and using but-2-ynoic acid (46 mg, 0.54 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (47 μL, 0.54 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (150 mg, 0.36 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (60 mg, 37%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[Br:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1>>[Br:23][C:24]1[N:25]=[CH:26][N:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:28]=1
Reactant: Brc1c[nH]cn1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (0.68 g, 2.0 mmol) and commercially available 4-bromo-imidazole (0.44 g, 3.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.79 g, 88%). MS (ISP) 452.9 [(M+H)+]; mp 191° C.