Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]1([C:30]([CH3:33])([CH3:32])[CH3:31])[O:10][CH:9]2[CH:11]([OH:29])[CH:12]([N:14]3[C:18]4[N:19]=[C:20]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])[N:21]=[CH:22][C:17]=4[S:16][C:15]3=[O:28])[O:13][CH:8]2[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:38]([O:37][C:35](=[O:36])[O:29][CH:11]1[CH:9]2[O:10][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:30]([CH3:33])([CH3:32])[CH3:31])[O:6][CH2:7][CH:8]2[O:13][CH:12]1[N:14]1[C:18]2[N:19]=[C:20]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])[N:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:28])([CH3:40])[CH3:39]
Reactant: CN(C)C=Nc1ncc2sc(=O)n(C3OC4CO[Si](C(C)(C)C)(C(C)(C)C)OC4C3O)c2n1
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)OC1C2O[Si](C(C)(C)C)(C(C)(C)C)OCC2OC1n1c(=O)sc2cnc(N=CN(C)C)nc21
Reaction time: 5 h
Yield: 50.9 %

Procedure:
N′-[3-(2,2-Di-tert-butyl-7-hydroxy-tetrahydro-furo[3,2-d][1,3,2]dioxasilin-6-yl)-2-oxo-2,3-dihydro-thiazolo[4,5-d]pyrimidin-5-yl]-N,N-dimethyl-formamidine (1.83 g, 3.68 mmol) was dissolved in DCM (18.4 mL) and DMAP (450 mg, 3.68 mmol) was added. Isopropyl chloroformate (7.37 mL, 1 M in toluene, 7.37 mmol) was added over 12 h via syringe pump. The reaction was stirred an additional 5 h following addition then concentrated in vacuo. The residue was submitted to flash chromatography (50-100% EtOAc-Hex) yielding 1.09 g (51%) of 14 as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.61 (1H, s), 8.60 (1H, s), 6.27 (1H, t, J=7.4 Hz), 6.10 (1H, d, J=7.9 Hz), 5.06 (1H, t, J=6.9 Hz), 4.61 (1H, septet, J=6.1 Hz), 4.49 (1H, t, J=10.5 Hz), 4.30-4.36 (1H, m), 3.93 (1H, dd, J1=5.3 Hz, J2=10.8 Hz), 3.14 (3H, s), 3.03 (3H, s), 1.14 (3H, d, J=6.2 Hz), 1.04 (3H, d, J=5.4 Hz), 1.04 (3H, s), 1.00-1.03 (18H, m)8.61 (1H, s), 8.60 (1H, s), 6.27 (1H, t, J=7.4 Hz), 6.10 (1H, d, J=7.9 Hz), 5.06 (1H, t, J=6.9 Hz), 4.61 (1H, septet, J=6.1 Hz), 4.49 (1H, t, J=10.5 Hz), 4.30-4.36 (1H, m), 3.93 (1H, dd, J1=5.3 Hz, J2=10.8 Hz), 3.14 (3H, s), 3.03 (3H, s), 1.14 (3H, d, J=6.2 Hz), 1.04 (3H, d, J=5.4 Hz), 1.04 (3H, s), 1.00-1.03 (18H, m). [M+H]+ @ m/z 583.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([O:10]CC)=[O:9])#[N:2].O.O[Li].O.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)cnc1C(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(C(F)F)c(C(=O)O)c1
Reaction time: 0.83 h
Yield: 66.7 %

Procedure:
To a solution of ethyl 5-cyano-2-(difluoromethyl)nicotinate (1.2 g, 5.3 mmol) in THF:water (20 mL:5 mL) was added LiOH.H2O (0.267 g, 6.3 mmol) at 0° C. and the reaction mass was stirred for 40-60 minutes. The reaction mass was acidified with dil. HCl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.37-7.72 (t, J=53.7 Hz, 1H), 8.24 (s, 1H), 9.30 (s, 1H), 14.25 (br s, 1H); MS (m/z): 199.34 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)([OH:3])=O.[B-](F)(F)(F)F.[CH3:26][N:27](C(ON1C(=O)C=CC=C1)=[N+](C)C)[CH3:28].CNC>CN(C=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:11]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[N:27]([CH3:28])[CH3:26])[NH:20][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a N2 atmosphere, 97.6 mg (0.338 mmol) of 6-carboxy-4-(3-chloro-anilino)-7H-pyrrolo[2,3-d]pyrimidine are introduced into 7 ml of DMF, and 119 mg (0.40 mmol) of TPTU and a solution of 164 mg (33% in ethanol; 1.2 mmol) of dimethylamine in 1 ml of DMF are added thereto. After 2 hours, a further 30 mg of TPTU is added to the reaction solution, which is then stirred at RT for 2 days, then poured into 30 ml of ice-water, stirred, filtered and washed with water to yield the title compound; HPLC: tRet (Grad20)=9.5; TLC-Rf =0.38 (CH2Cl2 /methanol [10:1]); FAB-MS: (M+H)+ =316.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:21]=[CH2:22])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[C:12]([CH2:21][CH3:22])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Reaction time: 72 h
Yield: 20 %

Procedure:
To a stirred solution 0.54 mmol 5-trifluoromethyl-6-vinyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 50 ml methanol was added 50 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen (0.6 bar positive pressure) for 72 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (20% yield). MS (m/e): 260.0 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (540 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1), 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (490 mg, 1.8 mmol, Amine-2, single enantiomer), and triethylamine (1.0 mL, 7.2 mmol) as a base in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16]O)=[CH:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:32]([CH2:16][C:15]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[N:12]=[CH:13][CH:14]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-n2nccc2CO)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(-n2nccc2CN=[N+]=[N-])cc1
Reaction time: 8 h

Procedure:
To a solution of [2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-methanol (4 mmol) and diphenylphosphoryl azide (0.95 mL, 4.4 mmol, 1.1 equiv) in THF (10 mL) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 4.4 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 5-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (0.344 g, 31% based on 4-(methylsulfonyl)phenylhydrazine hydrochloride, LCMS: (MH)+=278.0 (rt=1.36 min) and 3-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (75 mg, 7% based on 4-(methylsulfonyl)phenylhydrazine hydrochloride, LCMS: (MH)+=278.0 (rt=1.48 min)).
Reaction SMILES: ClC1C=CC(C(NN)=O)=CC=1.C(N=C=O)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=O)=[CH:20][CH:19]=1.NNC(N)=O.Cl>O1CCCC1.[OH-].[Na+]>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([CH:22]2[N:28]([CH2:29][CH3:30])[C:26](=[O:27])[N:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: CCN=C=O
Agent: Cl
Agent: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCN1C(=O)N=NC1c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a suspension of 4-chlorobenzhydrazide (98.5 g, 0.05 mole) in tetrahydrofuran (100 ml) at room temperature ethylisocyanate (4.2 g, 0.05 mole) was added slowly with magnetic stirring. The reaction was slightly exothermic and the reaction mixture turned to a thick paste. Stirring was continued an additional 30 min after which the solid was collected by suction-filtration and washed with a small amount of tetrahydrofuran and dried to provide 11.6 g (96.6% yield), of 1-(4-chlorobenzoyl)-4-ethyl semicarbazide as a white solid, m.p. 242°-243° C. The above semicarbazide (10 g, 0.0414 mole) was dissolved in 1N sodium hydroxide solution (100 ml) and was refluxed with stirring for 16 hr. The solution was cooled down to about 10° C. by an ice bath and was neutralized by conc. hydrogen chloride until pH 2. The resultant white solid was collected by suction-filtration and washed with water to give 8.65 g (93.5% yield) of 3-(4-chlorophenyl)-4-ethyl-1,2,4-triazolin-5-one as a white solid. m.p. 190°-197° C. A proton NMR spectrum was consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(OC)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccc(SC)cc2)cc1

Procedure:
A mixture of ethyl 1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (10.2 g) and potassium hydroxide (3.7 g) in methanol (60 ml) was refluxed for 30 minutes. The solvent was evaporated, and the residue was dissolved in water and washed with toluene. The aqueous layer was acidified, and the precipitates were collected and washed with ethyl acetate to give crystals of 1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid. (8.8 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:11])=[C:6]([N+:18]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:18])[C:7]([N:10]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:11])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: CN(C)CCCN(C)c1ccc(C2CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C2CC2)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-cyclopropyl-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (Step 2, 600 mg, 2.16 mmol) was dissolved in 22 mL MeOH. Palladium (115 mg, 0.108 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding the title compound as viscous red-brown oil. MS (M+H+)=248; Calc'd for C15H25N3=247.38.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:43]=[CH:42][CH:41]=[CH:40][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=2[C:14]([OH:25])=[C:13]1[N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:32][C@@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:13]2[N:12]([CH2:11][C:10]3[CH:40]=[CH:41][CH:42]=[CH:43][C:9]=3[Cl:8])[C:20]3[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=3[C:14]=2[OH:25])[CH2:27]1
Reactant: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](N)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (54 g) in chloroform (1 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (45 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[C:15]([OH:17])=O)=[CH:10][CH:9]=1.CN(C)C=O>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:15]2=[O:17])=[CH:12][CH:13]=1
Reactant: COc1cccc(CCC(C(=O)O)c2ccc(F)cc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(c1ccc(F)cc1)C2=O
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (3.3 ml.) was added to a stirred solution of the 2-p-fluorophenyl-4-m-methoxyphenylbutyric acid thus obtained (6.7 g.) and dimethylformamide (0.05 ml.) in toluene (50 ml.) and the mixture was stirred at laboratory temperature for 2 hours and then evaporated to dryness. The residue was dissolved in methylene chloride (100 ml.), the solution was stirred and cooled to -20° C. and stannic chloride (3.2 ml.) was added. The mixture was stirred for 2 hours and then poured into ice-water (250 ml.) and the mixture was extracted three times with methylene chloride (100 ml. each time). The combined extracts were washed with saturated aqueous sodium bicarbonate solution and then with water, dried and evaporated to dryness and the residue was stirred with methanol. The mixture was filtered and there was thus obtained as solid residue 2-p-fluorophenyl-3,4-dihydro-6-methoxy -naphthalen-1(2H)-one, m.p. 124-127° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O>C(OCC)C.C1COCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:27])=[CH:28][CH:29]=1)([O-:21])=[O:20]
Reactant: Brc1ccccn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution cooled at −78° C. of 2-bromopyridine (10.0 g) in diethylether (200 ml) was dropwise added 1.6M butyllithium hexane solution (39.6 ml) for 10 minutes. The mixture was stirred at −78° C. for 1 hour, and to the mixture was dropwise added a solution of 4-nitrobenzaldehyde in THF (50 ml). The reaction mixture was stirred at −78° C. for 3 hours, and to the mixture was added water (100 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/toluene=1/2) and re-crystallized from diisopropylether to give (4-nitro-phenyl)-(2-pyridyl)methanol (4.50 g) as orange crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[F-].[K+].CC#N>CCOC(C)=O.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.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Br)c(Cl)c(N)c1OC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(Cl)c(N)c1OC
Temperature: 115 °C
Yield: 47.9 %

Procedure:
To a 5 mL microwave vial were added methyl 4-amino-6-bromo-5-chloro-3-methoxypicolinate (200 mg, 0.677 mmol), 4-chlorophenylboronic acid (116 mg, 0.744 mmol), KF (102 mg, 1.760 mmol), and PdCl2(PPh3)2 (48 mg, 0.068 mmol). Subsequently, CH3CN (1.1 mL) and H2O (1.1 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave at 115° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (3 mL). The organic phase was separated, and the aqueous phase was washed with EtOAc (2×2 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was using a Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes to yield the title compound as a white solid (106 mg, 47%): mp 139-141° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.54 (m, 2H), 7.54-7.47 (m, 2H), 6.68 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H); ESIMS m/z 326.00 ([M−H]−).
Reaction SMILES: [OH-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH:11]([F:13])[F:12]>CCCCC.C(OCC)C.O.O1CCOCC1>[C:3]1([S:9][CH:11]([F:13])[F:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCC
Solvent: O
Product: FC(F)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A 6 ounce Fisher-Porter bottle was charged with 10.0 g (250 mmol) of sodium hydroxide, 13 mL of water, 15 mL of paradioxane, and 5.5 mL (54 mmol) of thiophenol. The bottle and overhead system were closed, the rapidly stirred mixture was heated to 60°-70° C. by means of an oil bath, and the system was charged to 50 psig with chlorodifluoromethane. Heating was continued for 1 hour, during which time the pressure gradually decreased and the system was occasionally recharged to 50 psig with chlorodifluoromethane. After cooling to room temperature, the system was opened and the reaction mixture was treated with 50 mL of water and 25 mL of diethyl ether. Filtration through glass wool paper followed by removal of the ether layer afforded an aqueous solution that was extracted with three 15 mL portions of diethyl ether. The ether layers were combined and concentrated in vacuo to give a residue which was dissolved in 50 mL of pentane. The pentane solution was washed with five 10 mL portions of water, dried (MgSO4), and concentrated in vacuo. Short path distillation of the residue gave 5.88 g (69% yield) of difluoromethyl phenyl sulfide: bp 24°-26° C. (1 torr): 1H NMR (CDCl3) 6.80 (t, 1H, JHF =57 Hz), 7.30-7.68 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl-].[K+].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)O)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 2-fluoronitrobenzene (2.33 g) was added fuming sulfuric acid (20 mL), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice and potassium chloride (10 g), and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g). To phosphoryl chloride (85 mL) were added 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g) and phosphorus pentachloride (2.82 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give the title compound (2.65 g).
Reaction SMILES: B#B.[CH2:3]([C@@:7]1([CH2:28][CH3:29])[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:10]=2[S:9][CH2:8]1)[CH2:4][CH2:5][CH3:6].Cl>C1COCC1>[CH2:3]([C@@:7]1([CH2:28][CH3:29])[NH:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:10]=2[S:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@]1(CC)CSc2cc(OC)c(OC)cc2C(c2ccccc2)=N1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[C@]1(CC)CSc2cc(OC)c(OC)cc2[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 39.6 %

Procedure:
A 1M solution of diborane in THF (200 ml) was added to a solution of the product (64.0 g) from step (m) in THF (350 ml). The reaction mixture was stirred at room temperature for a period of 17 hours, then 6N HCl (150 ml) was added and the solution was concentrated in vacuo to remove THF. The aqueous residue was basified with 50% NaOH and extracted with EtOAc. The EtOAc layer was separated, dried and concentrated in vacuo to afford an oil which was chromatographed on silica gel, using hexane: EtOAc (85:15) as eluant, to give the title product (25.5 g) as a beige solid, mp 64-66° C. 1H NMR consistent for proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])N(OC)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Mg]Br)[CH3:19].OS([O-])(=O)=O.[K+].CCOC(C)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:18][CH3:19])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccccc1[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccccc1C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (3.48 g, 14.2 mmol) in dry ether (150 mL) at 0° C. was added 2-methoxylphenylmagnesium bromide (1.0 M in THF, 17 mL, 17 mmol). The reaction was allowed to slowly warm to rt and stirred for 36 h. Then a solution of 1M KHSO4 and EtOAc were added and the aqueous portion was extracted once with EtOAc. The combined organic fractions were dried (Na2SO4) and concentrated to provide the title compound. This material was used in subsequent reactions without additional purifications. MS (ESI): mass calcd. for C16H21NO4, 291.1; m/z found, 236.1 [M-t-Bu]+. 1H NMR (CDCl3): 7.83 (dd, J=7.8, 1.8 Hz, 1H), 7.51 (ddd, J=8.5, 7.3, 1.8 Hz, 1H), 7.06-6.95 (m, 2H), 4.13-4.03 (m, 5H), 3.90 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]2([C:17]([CH3:21])([CH3:20])[CH2:18][F:19])[CH2:16][O:15]2)=[CH:10][CH:9]=1>C(O)CC>[F:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:14]([CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:23][CH:22]=1)([OH:15])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(CF)C1(COc2ccc(F)cc2)CO1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(CF)C(O)(COc1ccc(F)cc1)Cn1cncn1
Yield: 28.7 %

Procedure:
15.2 g (0.22 mol) of 1,2,4-triazole were added to 0.46 g (0.02 mol) of sodium in 200 ml of n-propanol. The solution was heated to the boil, and 48.5 g (0.2 mol) of 2-(4-fluorophenoxymethyl)-2-(fluoro-tert.-butyl)-oxirane, dissolved in 50 ml of n-propanol, were added dropwise. The reaction solution was stirred under reflux for a further 48 hours and was concentrated, and 200 ml of ethyl acetate and 100 ml of water were added to the residue. The organic phase was separated off, washed twice with water, dried over sodium sulphate and concentrated. The residue was dissolved in ether, and the solution was gassed with hydrogen chloride. The precipitate formed was filtered off under suction and washed with ether, and ethyl acetate/1N sodium hydroxide solution were added. The crude product obtained was purified over a silica gel column (mobile phase: methylene chloride/ethyl acetate, 2:1), and recrystallised from acetonitrile. 17.9 g (29% of theory) of 4-fluoro-2-(4-fluorophenoxymethyl)-3,3 -dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 97° to 99° C. were obtained.