Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)=O)(C)(C)C.BrC1C2[O:30][C:29]([F:33])([F:32])[O:28]C=2C=CC=1.C([C@@H]1OC1)Cl.[Cl:39][CH2:40][C@H:41]([OH:54])[CH2:42][C:43]1[C:51]2[O:50][C:49]([F:53])([F:52])[O:48][C:47]=2[CH:46]=[CH:45][CH:44]=1>>[Cl:39][CH2:40][C@H:41]([OH:54])[CH2:42][C:43]1[C:51]2[O:50][C:49]([F:53])([F:52])[O:48][C:47]=2[CH:46]=[CH:45][CH:44]=1.[F:32][C:29]1([F:33])[O:30][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][C@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:16]=2[O:28]1
Reactant: FC1(F)Oc2cccc(Br)c2O1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Agent: ClC[C@H]1CO1
Agent: O[C@@H](CCl)Cc1cccc2c1OC(F)(F)O2
Product: FC1(F)Oc2cccc(C[C@@H]3CNCCO3)c2O1

Procedure:
(R)-1-chloro-3-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but from 4-bromo-2,2-difluoro-benzo[1,3]dioxole and (R)-epichlorohydrin. Example 66 was prepared as described for example 1, intermediate (d), but using (R)-1-chloro-3-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-propanol, to obtain the desired morpholine example 66, as a colorless liquid, (0.214 g, 13.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=[C:11]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)cc1C
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cc(-c3ccc(C)c(C)c3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BO) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 436.1476 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4].[C:15]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][N:11]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:28])[CH:26]=3)[CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cncc2c1CCNC2
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)OC(C)(C)C)c1)C2
Temperature: 100 °C
Yield: 44591.2 %

Procedure:
A 1 L glass pressure vessel was charged with 5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (5.38 g, 0.028 mol) and 3-iodobenzoic acid tert-butyl ester (12.8 g, 0.042 mmol) in toluene (300 mL). The solution was stirred and sparged with argon for 10 min. Palladium(II)acetate (0.38 g, 0.00168 mol, 6 mole %) and cesium carbonate (18.3 g, 0.056 mol) were added and sparged with argon for an additional 10 min. (±)-2,2′-bis(diphenylphosphino)1,1′-binaphthalene (0.96 g, 0.00336, 12 mole %) was added and the vessel was sealed and heated at 100° C. overnight. HPLC analysis and TLC (ethyl acetate:hexane; 1:1) showed the reaction was complete. The reaction mixture was filtered and filter paper was washed with ethyl acetate (250 mL). The filtrate was washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (3×100 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography on silica gel (125 g) with anhydrous sodium sulfate (25 g) on top packed with hexane. The column was eluted with 100 mL portions of 10% ethyl acetate in hexane for fractions 1-5, 25% ethyl acetate in hexane for fractions 6-16, 35% ethyl acetate in hexane for fractions 17-24, and 40% ethyl acetate in hexane for fractions 25-32. All fractions checked by TLC. The product was eluted in fractions 19-28 to give the title compound (6.9 g, 67%) as a viscous oil. 1H NMR 60 MHz, (CDCl3), δ 9.0 (s, 1H), 8.6 (s, 1H), 7.4 (m. 5H), 4.5 (s, 2H), 4.0 (s, 3H), 3.6 (m, 4H), 1.7 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([F:27])=[C:20]([CH3:28])[C:10]=1[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O>[NH2:24][C:23]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:20]([CH3:28])=[C:21]([F:27])[CH:22]=1)[C:11]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: Cc1c(F)cc([N+](=O)[O-])c(OCc2ccccc2)c1C(=O)Oc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(N)c(OCc2ccccc2)c1C(=O)Oc1ccccc1
Yield: 108.1 %

Procedure:
A solution of compound 65 (700 g, 1.84 mol) in THF (7 L) was cooled to 12° C. and stirred while adding a solution of Na2S2O4 (1599 g, 9.18 mol) in water (7.0 L) was added to the reaction with stirring. The exotherm was controlled by addition rate so that the reaction mixture temperature was below 17° C. The reaction mixture was then allowed to stir for 15 hours prior to adding 15.3 L EtOAc. The layers were separated and the organic layer was washed with successively with water (2×4 L and brine (1×4 L). The organic was dried over Na2SO4 and concentrated to give 699 g of a brownish solid that was recrystallized from heptane/toluene to afford 532 g (82.7%) of desired compound 66 obtained as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH:20]1[CH2:19][CH:18]([C:13]2[C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:21]1
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 3-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)azetidine-1-carboxylate (5.19 g, 13.43 mmol) and DCM (20 mL) was added 2,2,2-trifluoroacetic acid (7.24 mL, 94 mmol). The mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo. DCM was added and evaporated to remove extra TFA. Ether was added and evaporated. The product was obtained as a yellow oil after drying on vacuum overnight. MS: 287 (M+1).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]([CH:10]([OH:19])[C:11]#[C:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:9])=[CH:3][CH:2]=1>[Pd].C(OCC)(=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([O:7][C@@H:8]([CH3:9])[CH:10]([OH:19])[CH2:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:6]=1
Reactant: C[C@H](Oc1ccc(-c2ccccc2)cc1)C(O)C#Cc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(-c2ccccc2)cc1)C(O)CCc1cccnc1

Procedure:
Prepared according to the method described in Example 1d) from (2S, 3RS)-2-(biphenyl-4-yloxy)-5-pyridin-3-yl-pent-4-yn-3-ol (4.16 g, Example 4c)), 10% palladium on charcoal (0.5 g) in ethyl acetate (100 ml) to give the sub-title compound as a white solid and as a 4:1 mixture of diastereomers (4.13 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12])[C:5]([N+:23]([O-])=O)=[CH:4][N:3]=1.Cl.CCOC(C)=O.CCOCC>CC(O)=O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:23][C:11](=[O:12])[C:10]([F:17])([F:16])[CH2:9][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
Compound ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate (1.0 g, 2.7 mmol) was dissolved in AcOH (10 mL) and then cooled in an ice bath. Iron powder (296 mg, 5.3 mmol) was added followed by the slow addition of HCl (1.5 mL, conc.). After 10 minutes the reaction was transferred to a heat bath and left to stir at 60° C. for 5 hours. The reaction was then cooled, the stir bar and unreacted iron removed by filtration through paper, and the solvent volume reduced by about 75% on a rotovap. The mixture was then diluted with ice water (15 mL) and EtOAc (20 mL), the layers separated, the aqueous layer washed with EtOAc (2×30 mL), the organic extracts combined, washed with sat. NaHCO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated to yield a brown syrup. Trituration with EtOAc (15 mL) and ether (100 mL) was used to coax out a light yellow solid (535 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.96 (m, 8H) 3.98 (t, J=11.49 Hz, 2H) 4.87 (q, 1H) 8.12 (s, 1H) 11.06 (br. s., 1H). [M+H] calc'd for C12H13ClF2N4O, 303. found 303.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][CH:18]=1>C(Cl)Cl.CCCCC>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:1])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: CC[Zn]CC
Reactant: C=C(C)c1ccc(Br)cc1
Solvent: ICI
Solvent: CCCCC
Solvent: ClCCl
Product: CC1(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 570.6 %

Procedure:
To a solution of diethyl zinc (20.30 ml, 1M solution in hexane, 20.30 mmol) in DCM (25 ml) at 0° C. was added a solution of trifluoroacetic acid (1.56 ml, 20.30 mmol) in DCM (10 ml) dropwise. The mixture was stirred at 0° C. for 20 min and then a solution of CH2I2 (1.64 ml, 20.30 mmol) in DCM (10 ml) was added. After stirring for an additional 20 min a solution of 1-bromo-4-isopropenylbenzene (346 mg, 1.76 mmol) in DCM (10 ml) was added. The reaction mixture was slowly warmed to rt and stirring was continued for 16 h. Pentane was added and the mixture was washed with 1M HCl, sat. NaHCO3, sat. Na2SO3 and brine. The organic layer was dried (MgSO4), filtered, concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane). The product (2.12 g, 86%) was isolated as a 4:1 mixture of product to methyleneiodide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.38 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 1.37 (s, 3H), 0.84-0.79 (m, 2H), 0.76-0.71 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccs1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Product: CCOc1cc(-c2cccs2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 145, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoro-methanesulphonyloxy-phenyl)-acetate by reaction with thiophene-2-boronic acid there was obtained the compound methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate, which was converted into methyl (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate hydrochloride.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O.CCOC(C)=O>[C:13]1([S:19][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCc2cc(Sc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-naphthalen-1-one (5.51 g, 33.56 mmol), benzenethiol (4.07 g, 3.79 mL, 36.92 mmol) and K2CO3 (9.28 g, 67.12 mmol) in 50 mL of N-methylpyrrolidinone (NMP) was heated to 80° C. under argon and stirred at 80° C. for 2 hours. The reaction mixture was poured into 500 mL of water and diluted with 300 mL of EtOAc. The layers were separated and the aqueous layer was extracted twice with 250 mL of EtOAc. The combined organic layers were washed with water, saturated brine, and then dried over MgSO4. The solvent was removed under reduced pressure to yield an oil which was eluted through silica gel using hexanes/EtOAc (9:1). Removal of solvent under reduced pressure provided 8.05 g (31.65 mmol, 94.31%) of 6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a pale yellow oil. MS: 255 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:12].O>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(C(F)(F)F)cc1
Yield: 58.4 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (408 mg). and 2-bromo-4'-trifluoromethyl-acetophenone (824 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 45 mins. Water (100 ml) was added and the precipitate was collected. This solid was crystallised from acetone to give the title pyrimidinone (571 mg,); m.p. 243°-245°; λmaxEtOH 235.5 nm (ε 20040), 282 nm (ε 1880), 333.5 nm (ε 1860), λinf 287.5 nm (ε 1790).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)=[O:5])#[N:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[C:1]([C:3](=[CH:20][N:21]([CH3:23])[CH3:22])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1ccccc1-n1cccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1-n1cccc1

Procedure:
As for Example 1, 2-cyano-2'-(1-pyrrolyl)acetanilide, colorless needles, m.p. 143°-144° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2-cyano-3-dimethylamino-2'-(1-pyrrolyl)acrylanilide as yellow crystals, m.p. 169°-171° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Br:43][C:44]1C=[CH:48][CH:47]=[CH:46][C:45]=1CBr>>[Br:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:15]=1[CH2:14][N:11]1[C:9]2[N:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([N:16]3[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]3)[C:8]=2[N:13]=[N:12]1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: BrCc1ccccc1Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3Br)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-(bromomethyl)benzene and isolated as colorless gum (6.6 mg, 35%). MS(m/e): 451.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=2)[N:25]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[C@@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](C(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(C)(C)C)nc12
Reaction time: 0.75 h
Yield: 39 %

Procedure:
To (S)-4-tert-butyloxycarbonyl-2-tert-butylpiperazine (640 mg, 2.6 0 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 115 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (780 mg, 3.69 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 3d and at 55° C. for 24 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The residue was purified by column chromatography (silica gel, 33% EtOAc in hexanes) to afford (S)-methyl 2-(4-tert-butyloxycarbonyl-2-tert-butyl-piperazin-1-yl)benzoxazole-4-carboxylate (0.42 g, 39%) as a yellow solid. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13]O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS([Cl:37])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][Cl:37])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of (R)-tert-butyl(1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.80 g, 8.0 mmol) in CH2Cl2 (20 mL) was added Et3N (1.60 g, 16 mmol) and MsCl (1.40 g, 12.0 mmol) dropwise at −10° C. under N2. The mixture was stirred at rt overnight. The mixture was quenched with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered, concentrated to afford (R)-tert-butyl(1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.0 g, 100% yield) as a yellow solid, which was used for the next step without further purification. LC-MS m/z 369.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.37-7.28 (m, 3H), 7.22-7.20 (m, 2H), 5.27-5.18 (m, 1H), 4.93-4.86 (m, 1H), 4.64-4.39 (m, 2H), 3.85-3.66 (m, 2H), 3.61-3.39 (m, 2H), 2.03-1.97 (m, 1H), 1.45 (s, 9H), 0.98 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)[OH:22].N([O-])=O.[Na+].F[B-](F)(F)F.[Na+]>O>[OH:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Sc1ccccc1O
Reaction time: 0.33 h

Procedure:
Suspend 10.15 g (35 mmoles) of the amino acid of Step A in 75 ml of water and add 4 ml concentrated sulfuric acid (7.36 g, 75 mmoles, 150 meq). Cool the mixture in an ice-bath and add 3.657 g (53 mmoles) of sodium nitrite in portions at 0°-5° C. Stir the suspension in the cold for 20 minutes. Add 10 g (91 mmoles) of sodium fluoroborate and stir for an additional 20 minutes. Separate the precipitated crude diazonium fluoroborate, suspend the precipitate in 250 ml of 50% sulfuric acid and heat in an oil bath at 90°-100° C. for 45 minutes. Cool the mixture and separate the precipitate. (Yield: 7.76 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][NH2:23])[C:5](=[O:20])[C:6]1[C:14]([I:15])=[C:13]([NH:16][CH3:17])[C:12]([I:18])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:19].[Br:24][CH:25]([CH3:29])[C:26](Br)=[O:27]>CC(N(C)C)=O>[Br:24][CH:25]([CH3:29])[C:26]([NH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][NH:23][C:26](=[O:27])[CH:25]([Br:24])[CH3:29])[C:5](=[O:20])[C:6]1[C:14]([I:15])=[C:13]([NH:16][CH2:17][C:26](=[O:27])[CH:25]([Br:24])[CH3:29])[C:12]([I:18])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:19])=[O:27]
Reactant: CC(Br)C(=O)Br
Reactant: CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCN)CCN)c1I
Solvent: CC(=O)N(C)C
Product: CC(Br)C(=O)CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCNC(=O)C(C)Br)CCNC(=O)C(C)Br)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (76.1 mmol) of N,N-bis-(2-aminoethyl)-5-(methylamino)-2,4,6-triiodoisophthalic acid amide is dissolved in 500 ml of dimethylacetamide, and 75.5 g (350 mmol) of 2-bromopropionic acid bromide (Aldrich) is added in drops over 15 minutes at 0° C. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6](=[O:15])[C:7]([C:13]#[N:14])=[C:8]([S:11][CH3:12])SC.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[NH:25][NH2:26]>O>[CH3:4][O:5][C:6]([C:7]1[C:8]([S:11][CH3:12])=[N:26][N:25]([C:18]2[C:19]([Cl:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[C:13]=1[NH2:14])=[O:15]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)C(C#N)=C(SC)SC
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reaction time: 8 h

Procedure:
An ethanol (3.5 l) solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid methyl ester (454.3 g, 2.23 mol) and 2,4,6-trichlorophenylhydrazine (472.7 g, 2.23 mol) was vigorously refluxed for 1.5 hours. The reaction mixture was allowed to stand overnight at ambient temperature. Water (850 ml) was added, and the resulting mixture was briskly stirred for 30 minutes. The granular precipitate was filtered and washed with a water/ethanol(1:3 in volume)solution (1 l). The air-dried product was further dried under vacuum (45° C.) for 2 days to afford the title compound as a yellow crystalline solid, m.p. 160°-162° C.