Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:31]([O:33][CH3:34])=[O:32])[CH3:10].O[CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C@H:9]([O:11][C:12]2[CH:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][C:24]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:25][C:20]=4[N:19]=[CH:18]3)[S:14][C:13]=2[C:31]([O:33][CH3:34])=[O:32])[CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(OC(F)(F)F)ccc32)cc1O[C@H](C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a slurry of methyl 3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 25, 0.18 g, 0.35 mmol) and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (0.21 g, 1.0 mmol) in DCM (10 mL) was added triphenylphosphine (0.18 g, 0.70 mmol) and di-tert-butylazodicarboxylate (0.16 g, 0.70 mmol). The clear, yellow solution was stirred for 1 h, and then silica gel (3 g) was added. The volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 50% EtOAc:CH2Cl2) to give 0.20 g (0.29 mmol) of 1,1-dimethylethyl 4-[(2-chloro-3-{(1R)-1-[(2-[(methyloxy)carbonyl]-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-3-thienyl)oxy]ethyl}phenyl)oxy]-1-piperidinecarboxylate which was then dissolved in 5 mL of DCM and TFA (1 mL, 5.9 mmol) was added. After 1 h the volatiles were evaporated under reduced pressure and the residue was dissolved in a solution of 7 N ammonia in MeOH (10 mL). The mixture was heated in a sealed tube to 80° C for 40 h and then cooled to rt. Silica (1 g) was added, the volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide; DCM) to afford 0.14 g (69%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.42 (d, J=8.79 Hz, 1H), 7.30 (m, 2H), 7.15 (d, J=7.87 Hz, 1H), 7.10 (d, J=7.87 Hz, 1H), 6.97 (s, 1H), 6.05 (q, J=6.29 Hz, 1H), 4.56 (m, 3H), 3.06 (m, 2H), 2.69 (m, 2H), 1.95 (m, 2H), 1.77 (d, J=6.23 Hz, 3H), 1.71 (br m, 2H); MS (ESI): 581 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)[CH3:26]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([NH:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:32]3[CH:33]=[CH:34][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:30][CH:31]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(NCCC)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-15% EtOAc-hexanes) afforded 40.0 mg (61%) of the title compound as an orange oil.
Reaction SMILES: O[CH:2]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[O:19]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]=2[NH:10]1
Reactant: O=c1[nH]c2c(c3ccccc13)C(O)c1ccccc1-2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a stirred solution of the alcohol 3a (0.35 g, 1.4 mmol) in trifluoroacetic acid (10 mL) was added at room temperature triethylsilane (0.812 g, 7 mmol) and the reaction mixture was stirred for 24 h. Trifluoroacetic acid was evaporated in vacuo and EtOAc was added to the resulting crude product. The resulting solid was filtered and washed with H2O and EtOAc to provide the above-titled compound 6 (0.285 g, 87%). 1H NMR (DMSO-D6): δ 3.89 (s, 2H), 7.30-7.47 (m, 3H), 7.59 (d, J=6.9 Hz, 1H), 7.72-7.74 (m, 2H), 7.98 (d, J=7.8 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 12.31 (s, 1H); 13C NMR(DMSO-D6): δ 33.51, 116.50, 120.19, 124.01, 125.51, 125.55, 126.42, 127.50, 127.68, 128.56, 133.45, 136.39, 137.53, 140.18, 143.80, 163.46; MS (ES−): m/z 232.1 (M−1); Anal. Calcd for C16H11NO: C, 82.38; H, 4.75; N, 6.00. Found: C, 81.79; H, 4.45, N, 5.99.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([S:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=2)=[C:12]([Cl:28])[CH:11]=1)C.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:28][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[S:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Yield: 103.2 %

Procedure:
A solution of (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (86) (2.98 g, 5.99 mmol) in glacial acetic acid (60 mL) was treated with sodium acetate (2.46 g, 29.95 mmol). The resulting mixture was heated to 120° C. for 3 h. At this time, LCMS indicated complete consumption of the starting material and conversion to product. The reaction was cooled to 25° C., poured onto water (200 mL) and was extracted with ethyl acetate (2×150 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried with magnesium sulfate, filtered and concentrated under vacuum to give an orange solid. This solid was dissolved in a 1:1 methylene chloride:hexanes mixture and concentrated in vacuo three times. It was then dissolved in a 1:1 methylene chloride: methanol mixture and concentrated under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (87) (2.79 g) as an orange solid. The material was used without further purification; ES(+)-HRMS m/e calcd for C17H12Cl2N6O3S (M+H)+ 451.0142, found 451.0143. Exact Mass=450.0069; Molecular weight=451.29
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][C:20]([F:21])=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
To the mixture of 6-chloro-2-oxindole (5.3 g, 32 mmol) (Crescent) and 3-chloro-4-fluorobenzaldehyde (5 g, 32 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.7 g, 32 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 8 g, 82%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([O:22][C:23]([N:25]([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([O:22][C:23]([N:25]([CH3:30])[CH2:26][C:27]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CN(C)C(=O)OC(C)(C)C)C2
Yield: 69.7 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while being cooled on ice. To the obtained mixture, N-tert-butoxycarbonyl-N-methylglycine (2.0 g, 11 mmol), WSC.HCl (2.0 g, 11.0 mmol), and HOBT (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was subjected to distillation under reduced pressure. The resultant residue was extracted with chloroform after the pH was turned to acidic with HCl. The organic phase was washed with saturated aqueous NaCl solution, and dried. The solvent was distilled off under reduced pressure. The resultant residue was recrystallized from chloroform--methanol--ether. As a result, 2.8 g of the title compound was obtained as colorless powdery crystals (69.0%)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[H-].[Na+]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:1]([O:8][C:9]([N:11]([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=1)[C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C(Nc1cnc2n(c1=O)[C@H](C(=O)O)CC2)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCc2ncc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OCc3ccccc3)c(=O)n21
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.5 %

Procedure:
To a mixture of acid 1i (4.50 g, 13.7 mmol) in 70 mL THF at 0° C., was added 3-(trifluoromethyl)benzyl bromide (8.35 mL, 54.7 mmol), NaH (60% dispersion in oil, 1.64 g, 41.4 mmol), and TBAI (100 mg, catalytic). The reaction was stirred at rt for 15 h, then quenched with the addition of 50 mL H2O. The volatile solvents were removed by rotary evaporation and the aqueous solution obtained was partitioned with Et2O. The organic phase was extracted with 20% sat. NaHCO3 (3×). The combined organic extract was acidified with 1N HCl and extracted with EtOAc (5×). The combined organic extract was washed (brine), dried (Na2SO4), and concentrated to afford 6.18 g (93%) of the 3-(trifluoromethyl)benzyl amine (12a), which was used in the following step without additional purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC>C(Cl)Cl>[CH3:27][O:31][N:32]([CH3:33])[C:11]([C:9]1[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[N:10]=1)=[O:13]
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (2.0 g, 10.2 mmol) in DCM (45 mL), DIPEA (8.8 mL, 51.2 mmol) followed by TBTU (3.9 g, 12.3 mmol) is added. The mixture is stirred at rt for 30 min before N,O-dimethylhydroxylamine (1.20 g, 12.3 mmol) is added. The mixture is stirred at rt for 18 h before it is diluted with DCM, washed with sat. aq. NaHCO3, followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:2 to give 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (2.39 g) as a yellow oil; LC-MS: tR=0.66 min, [M+H]+=239.03; 1H NMR (D6-DMSO): δ 1.14 (d, J=6.5 Hz, 6H), 2.28 (s, 3H), 3.23 (s, 3H), 3.67 (s, 3H), 4.05 (m, 1H), 6.50 (s br, 1H), 7.12 (s br, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][NH:3][CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5]
Reactant: CON=C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 50 h
Yield: 62.3 %

Procedure:
To a stirred solution of trans 1-[2-(2,4,5-trichloro-thiophen-3-yl)cyclopropyl]-ethanone O-methyl-oxime (2.85 g; 9.5 mmol) prepared as described in example P24, in acetic acid (20 ml) at ambient temperature was added portionwise sodium cyanoborohydride (1.80 g; 29 mmol). The reaction mixture was stirred for 50 hours at ambient temperature then poured on sodium hydroxide solution (0.5M; 150 ml) and extracted with dichloromethane (3×50 ml). Combined organic layers were washed with sodium hydroxide solution (0.5M; 100 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 80:20) to afford 1.78 g (62% of theory) of trans O-methyl-N-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethyl}-hydroxylamine as a mixture of diastereomeres in form of a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[OH-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1>C(COC)OC>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([CH2:18][N:2]([CH3:1])[C:3]2[CH2:7][O:6][C:5](=[O:8])[CH:4]=2)=[CH:16][CH:17]=1
Reactant: CNC1=CC(=O)OC1
Reactant: ClCc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CN(Cc1ccc(Cl)nc1)C1=CC(=O)OC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
30 g of 4-(methylamino)furan-2(5H)-one (Example 11) are initially charged in 450 ml of dimethoxyethane at room temperature. Subsequently, 12.6 g of sodium hydroxide are added and, at 40° C., 225 g of a 20% solution of 2-chloro-5-(chloromethyl)pyridine in dimethoxyethane are metered in. The mixture is stirred at 50° C. for a further 6 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 300 ml of water. The solids are filtered off, washed with 150 ml of water and dried under reduced pressure. 58.7 g of 4-([[6-chloropyridin-3-yl]methyl](methy)amino)furan-2(5H)-one are obtained with a purity of 94% (this corresponds to 87% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O.[BH4-].[Na+]>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.CCO.O.C1(C)C=CC=CC=1>[F:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=Cc1cccc(B(O)O)c1F
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: [BH4-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(CO)c2F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Under argon atmosphere, sodium carbonate (1000 mg) and tetrakis(triphenylphosphine)palladium (170 mg) were added to a mixture of (2-fluoro-3-formylphenyl)boronic acid (700 mg), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (1000 mg), toluene (15 ml), EtOH (5 ml) and water (5 ml) followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH, and NaBH4 (120 mg) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then EtOAc and water were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (637 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([OH:15])[C@@H:5]([NH2:14])C1C=CC(F)=C(F)C=1.C(N(CC)C(C)C)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:4]1[O:15][C:27](=[O:29])[NH:14][CH2:5]1)=[O:16]
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccc(F)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CNC(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,3S)-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol) in 250 mL tetrahydrofuran at 0° C. was added N,N-diisopropylethylamine (8.75 mL, 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred at 0° C. for 30 min when it was poured over ethyl acetate (200 mL) and saturated sodium carbonate solution (100 mL). The layers were separated, the organic layer washed with saturated sodium carbonate solution (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow oil. The material svas triturated with 25% ethyl acetate/hexane to provide (4S,5R)-4-(3,4-difluorophen)fl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester. The recovered mother liquor was passed through silica (50% ethyl acetate/hexane) to give additional product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].[OH-].[Na+]>O.C(O)(=O)C>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2)=[CH:7][CH:8]=1
Reactant: N#C[O-]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(=O)[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a suspension of 2-amino-4-methylbenzoic acid (58.9 g, 390 mmol) in water (1.5 L) and glacial acetic acid (50 ml) was added dropwise a solution of potassium cyanate (80.5 g, 993 mmol) in water (300 ml). After completion of the addition and stirring at room temperature for half an hour, sodium hydroxide pellets (500 g) were added at such a rate that the temperature was kept below 50° C. (with ice cooling). During the addition the mixture became a clear solution for a short period, and upon continuation of the sodium hydroxide addition a cream precipitate started forming. The suspension was cooled to 0-5° C. and the precipitate was collected by filtration and washed twice with water (150 ml). The solid was poured in water (1 L) and was acidified with concentrated aqueous HCl (30%, 150 ml). The solid was collected by filtration and washed with water (150 ml) to yield 7-methylquinazoline-2,4(1H,3H)-dione (57.0 g, 83%) after drying at 45° C. under vacuum.
Reaction SMILES: [Ca].F[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:3]1([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: Fc1ccccc1
Agent: [Ca]
Product: OC1(c2ccccc2)CCCCC1
Yield: 85 %

Procedure:
Reactions of aryl halides with reactive calcium required slightly higher temperatures, up to -30° C. for aryl bromides and up to -20° C. for aryl chlorides. The aryl calcium compounds are very stable at room temperature. Reactions of m-bromotoluene, m-bromoanisole, and p-chlorotoluene with the soluble highly reactive calcium complex gave the corresponding arylcalcium reagents in quantitative yields based on the GC analyses of reaction quenches. The 1,2-addition of these arylcalcium compounds with ketones gave the alcohols in excellent yields (76%, 79% and 86%, respectively). The soluble highly reactive calcium readily reacted with fluorobenzene at room temperature to form the corresponding organometalic compound which underwent an addition reaction with cyclohexanone to give 1-phenylcyclohexanol in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1.CC1ON=C(CCC(OC)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1
Reactant: Cc1cc(CCCCCCCCBr)on1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Agent: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{8-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]octyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-Cl, Y=(CH2)8, oxazole at 4-position] was prepared from 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole (Example 13b) and 5-(8-bromooctyl)-3-methylisoxazole (Example 18a) according to the procedure of Example 9, part (d), and was obtained in the form of a colorless solid, m.p. 63°-64° C. when recrystallized from ether.