Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][Br:6])[CH2:3][OH:4].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C@H:2]([CH2:5][Br:6])[CH2:3][O:4][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](CO)CBr
Product: C[C@H](CBr)COCc1ccccc1

Procedure:
The starting material, 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate, was prepared as follows: (S)-2-methyl-3-bromopropanol was alkylated with benzyl bromide to produce (S)-2-methyl-3-bromo-1-benzyloxypropane, which was then combined with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropanol, followed by hydrogenation with 10% Pd/C to remove the benzyl protecting group. The title compound was prepared by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (0.7 g, 2.58 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate (1.7 g, 2.58 mmol) essentially as described in Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography, eluting with 10:1 hexanes/ethyl acetate, and was recrystallized from heptane, followed by Kugelrohr distillation (b.p. 180-190° C. at 0.02 torr; yield 1.28 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([O:8][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(OS(C)(=O)=O)CC(C)(C)O1
Yield: 102.8 %

Procedure:
In a manner similar to the method described in example 32a, 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol (5.5 g, 35 mmol) was reacted with methanesulfonyl chloride (6 g, 52 mmol, Aldrich) and triethylamine in dichloromethane to give methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl ester as a yellow oil (Yield 8.5 g, 100%). The starting material 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol was prepared according to the procedures described by Nemeroff, N. et al in J. Org. Chem. 1978, 43(2), 331-334 with slight modification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:32](=[O:34])[CH3:33])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of product from step 3 (105 mg, 0.23 mmol) in methylene chloride (1 ml) was added triethylamine (93 mg, 0.92 mmol), acetyl chloride (18 mg, 0.23 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 8 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 75 mg (80%) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2C(C3C=C(NC(=O)C(F)(F)F)C=CC=3)=NN3C=CC=C(F)C=23)C=CN=1.[F:55][C:56]1[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[C:57]=1[C:58](Cl)=[O:59].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:21][C:58](=[O:59])[C:57]4[C:56]([F:55])=[CH:64][CH:63]=[CH:62][C:61]=4[F:65])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1
Agent: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To the solution of 3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.31 g) (prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide obtained Example 168, Step B using a protocol similar to that described in Example 168, Step C) in THF (10 mL) was added 2,6-difluorobenzoyl chloride (0.19 g). The reaction was kept stirring at rt for 0.5 h and worked up with sat. NaHCO3 solution (8 mL). After extraction with EtOAc (2×10 mL), drying with Na2SO4, and concentration, the crude mixture was purified through silica gel column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide as a yellow solid (0.43 g, 96%). ESIMS (M+H)+=480.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:25]([O-])=O)=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.C(O)=O>C1COCC1.CO.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CO
Product: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Reaction time: 20 h
Yield: 88.6 %

Procedure:
A mixture of 1-[3-(2-chloro-ethoxy)-2-nitro-phenyl-methanesulfonyl]-naphthalene (1.24 g, 3.5 mmoles) and 10% Pd/C in THF (20 mL), methanol (5 mL), and formic acid (5 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2Cl2 to afford the title compound as an off-white solid (1.0 g, 3.1 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([OH:22])=O)=[N:10]2)=[CH:5][CH:4]=1.[N:23]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[N+:24]=[N-:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]3[CH2:27][CH2:26][N:23]=[N+:24]=[N-:25])=[O:22])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cn1
Reactant: [N-]=[N+]=NCCC1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3CCN=[N+]=[N-])cc2-c2ccccc2)cn1
Reaction time: 14 h

Procedure:
1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carboxylic acid (191 mg) obtained from Referential Example 41, 2-(2-azidoethyl)piperidine (100 mg) obtained from Referential Example 80, 1-hydroxybenzotriazole (88 mg), and triethylamine (316 μL) were dissolved in methylene chloride (10 mL). To the resultant mixture, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (186 mg) was added at room temperature, followed by stirring for 14 hours. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The residue obtained by removal through evaporation of the solvent under reduced pressure was purified through silica gel thin-layer chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (227 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)CCl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-5-cyano pyridine (2.0 g) in dry dichloromethane (17 mL) under nitrogen at 0° C. was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50% EtOAc/cyclohexane. The relevant fractions were combined and evaporated to give the title compound (2.17 g) as a light brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]C([O-])(C)C.[Na+].CCCCCC.CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-3-methyl-piperidin-4-one (7.0 g, 34 mmol) and Mel (2.4 mL) in THF (100 mL) was added NaOt-Bu (4.2 g, 44 mmol) at 0° C. The reaction was slowly allowed to warm to room temperature and stirred overnight. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. Flash column chromatography (Hexane/EtOAc, gradient) of the residue gave 1-benzyl-3,3-dimethyl-piperidin-4-one, which was converted into 1-benzyl-3,3-dimethyl-piperidin-4-ylamine (2) using the same procedure as in Scheme 1-1. LCMS m/z: 220 (M+H)+. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]Br.[OH-].[Na+]>C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Cc1ccc(N)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cnc(N)c(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-picoline (5 g) in acetic acid (40 mL) at r.t. was added bromine (2.6 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10N) at 0°0 C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:2 v/v) of the residual solid provided the title compound as a pale yellow solid (7.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]=[CH2:13])[N:6]1C(OC(C)(C)C)=O)=[O:4].S(Cl)([Cl:23])=O>CO>[ClH:23].[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]=[CH2:13])[NH:6]1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: C=CCOC1CCC(C(=O)OC)N1C(=O)OC(C)(C)C
Solvent: CO
Product: C=CCOC1CCC(C(=O)OC)N1
Product: Cl
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5-allyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 4, (7.28 g, 27 mmol) in MeOH is added thionyl chloride (4 mL, 54 mmol). The solution is stirred overnight and the solvent removed in vacuo to afford 4.25 g (95% yield) of the desired product as a dark yellow crystal. 1H-NMR (300 MHz, CDCl3): δ 11.47 (s, 1H), 8.15 (s, 1H), 5.81 (m, 1H), 5.23 (m, 2H), 4.55 (s, 1H), 3.85 (s, 3H), 2.88 (m, 1H), 2.59–2.42 (m, 2H), 2.24 (m, 1H), 1.81 (m, 1H). 13C-NMR (75.5 MHz, CDCl3): δ 170.0, 132.7, 132.3, 120.2, 119.6, 60.6, 60.2, 59.4, 58.9, 53.9, 36.6, 29.5, 29.2, 28.3. ESI MS 170.13 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:16]1[C:21]([CH:22]=O)=[CH:20][C:19]2[O:24][CH2:25][O:26][C:18]=2[CH:17]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:22][C:21]3[CH:16]=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cn(-c2ccc(OCCNCc3ccc4c(c3)OCO4)cc2)cn1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To 2-[4-(imidazol-1-yl)phenoxy]ethylamine (4.0 g, 20 mmol) dissolved in MeOH (150 mL) was added piperonal (3.0 g, 20 mmol) and acetic acid (1.5 mL). After stirring for 1 h, NaBH3CN (2.6 g, 40 mmol) was added. After stirring for 18 hour, the solvent was removed in vacuo and the residue was chromatographed on silical gel with 2% methanol in methylene chloride to give 3.5 g of N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine, 1H NMR (DMSO-d6) 8.12 (s, 1), 7.62 (s, 1), 7.54 (d, 2), 7.08–7.02 (m, 3), 6.90 (s, 1), 6.82–6.75 (m, 2), 5.94 (s, 2), 4.03 (t, 2), 3.62 (s, 2), 3.32 (s, 1), 2.80 (t, 2) ppm.
Reaction SMILES: [CH2:1]([C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CCC.C(C(O)=O)CCCCCCCCCCCCCCCCCCCCCCCCC.C(C(O)=O)CCCCCCCCCCCCCCCCCCCCCCCCCCC>>[C:25]([OH:27])(=[O:26])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)O

Procedure:
A polymer dispersion of carboxylic acid silver salts - carboxylic acids - silver bromide (Composition H - 6) was produced in the same manner as in Example 1 except that a mixture of 204 g of behenic acid and 164 g of an equimolar mixture of C24H49COOH, C26H53COOH and C28H57COOH was used instead of the mixture of 272 g of behenic acid and 82 g of C26H53COOH.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)(C)(C)C.[ClH:28].C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[ClH:28].[NH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)OC(C)(C)C)s3)n2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1

Procedure:
[5-(2-m-Tolylamino-pyrimidin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester was treated with 4 N HCl in 1,4-dioxane for 6 hours or 20% TFA in DCM for 2 hours. The solution was dried in vacuo to afford [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine HCl salt. The amine salt was also neutralized by drying down the HCl/dioxane solution, redissolving in EtOAc and washing with saturated NaHCO3 (2×) and brine (1×) and dried over Na2SO4. Concentrated and redissolved and dried down 2× from DCM to obtain an orange foam [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (quantitative). MS: m/z 283 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10]N.[C:12](#[N:14])C>>[I:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:12]=[N:14][N:10]=[C:2]2[CH:7]=1
Reactant: NN
Reactant: CC#N
Reactant: Fc1cc(I)ccn1
Solvent: O
Product: Ic1ccn2cnnc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1 g of 2-fluoro-4-iodo-pyridine and 5 ml of hydrazine monohydrate were dissolved in 6 ml of acetonitrile, and the mixture was stirred at 80° C. for 2 hours, and the solvents were distilled outunder reduced pressure. 5 ml of dimethylformamide and 3 ml of ethyl orthoformate were added to the residues, stirred at 150° C. for 2 hours, cooled down to room temperature and the reaction was stopped after adding water. The products were extracted with chloroform, and after drying with anhydrous sodium sulfate, the solvents were distilled outunder reduced pressure. The obtained residues were washed with ethyl acetate and 680 g of the above compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:19](Cl)=[O:20])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[C:26]([C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:24]=1[OH:25])[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
A suspension of 9.2g (0.061 mole) of p-aminophenylacetic acid in 150 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with water and chilled. The resulting precipitate was collected and recrystallized from a mixture of ethanol and water to give 1.32g of yellow crystalline 4-(3,5-di-t-butyl-4-hydroxybenzamido)phenylacetic acid, m.p. 253°-254° C. Analysis: Calculated for C23H29NO4 : %C, 72.0; %H, 7.6; %N, 3.6; Found: %C, 72.0; %H, 7.7; %N, 3.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(OCC)=O>O.C(#N)C>[C:25]1(=[O:34])[N:12]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH3:11])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCC(N)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 38.1 %

Procedure:
To a stirred solution of 1-(4′methoxyphenyl)propylamine (2.5 grams, 15.2 mmol) and sodium carbonate (1.74 grams, 16.4 mmol) in a mixture of water (50 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (3.34 grams, 15.2 mmol). The resulting suspension was stirred for 4.5 hours at room temperature, the acetonitrile was removed in vacuo and a solid formed. The slurry was filtered and the solid was washed with water and air dried to afford 1.73 grams (39%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 1.71 grams (38%) of the product as white crystals: mp 85-86° C.; 1H NMR (DMSO-d6) δ7.92-7.79(m, 4H), 7.46-7.28(m,2 H), 6.97-6.83(m, 2 H), 5.19-5.06(m, 1 H), 3.72(s, 3H), 2.56-2.13(m, 2 H), 0.87(t, J=7.3 Hz, 3 H);13C NMR (DMSO-d6) δ167.8, 1.5, 134.6, 131.7, 131.0, 128.6, 123.1, 113.7, 55.2, 54.9, 23.8, 11.3. Anal. Calculated for C18H17NO3. Theoretical: C,73.20; H,5.80; N, 4.74. Found: C,73.24; H, 5.74; N, 4.86. HPLC 100%.
Reaction SMILES: [O:1]=[S:2](Cl)Cl.[C:5]([O:9][C:10]([NH:12][C@@H:13]([C@H:24]([OH:26])[CH3:25])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.I([O-])(=O)(=O)=[O:34].[Na+]>CC#N.[Ru](Cl)(Cl)Cl.O>[CH3:25][C@H:24]1[O:26][S:2](=[O:1])(=[O:34])[N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[C@@H:13]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@H]1OS(=O)(=O)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
A solution of SOCl2 (24.2 ml, 332 mmol) in dry MeCN (240 ml) under nitrogen was cooled to −5° C., then (2S,3R)-benzyl 2-(tert-butoxycarbonylamino)-3-hydroxybutanoate (50 g, 162 mmol) in dry MeCN (120 ml) was added dropwise over 10 min, followed by dropwise addition of pyridine (65.4 ml, 808 mmol) to maintain the internal temp <0° C. After stirring for 10 min, cooling was removed and the reaction mixture was stirred for 3 h, then concentrated, mixed with EtOAc (1130 ml) and H2O (320 ml), and stirred at RT for 20 min. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine 3 times, then concentrated. The residue was dissolved in CH3CN (320 ml), and, at 5° C., ruthenium(III) chloride (77.1 mg, 372 μmol) was added, followed by sodium periodate (68.8 g, 321 mmol). After stirring for 10 min, H2O (320 ml) was added over about 1 min. The mixture was stirred at RT for 1.5 h, then filtered to remove solid salts, treated with brine (320 ml), and extracted with EtOAc twice. The organic layer was washed with brine, dried over Na2SO4, filtered through a bed of 3 layers of celite+silica gel+Na2SO4, and concentrated to afford 4-benzyl 3-tert-butyl(4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide (50.1 g, 84%) as a slightly brownish oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[N:19]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]([CH3:23])=[CH:21][CH:20]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](OCC)=[O:37]>C1COCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[O:37])[CH2:23][C:22]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: Cc1ccnc2ccccc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccnc2ccccc12)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
To a solution of diisopropylamine (44.9 mL, 320 mmol) in THF (500 mL) at −78° C. add 1.6 M n-butyl lithium in hexane (200 mL, 320 mmol). Stir for 10 minutes and add dropwise a solution of lepidine (42.9 g, 300 mmol) in THF (200 mL) over 20 minutes at −78° C. and quickly add a solution of ethyl picolinate (48.3 g, 320 mmol). Allow the reaction to warm slowly to 0° C. and quench by pouring into water (1 L). Add ethyl acetate (1 L). Dissolve residual solids by adding Acetic acid (20 mL). Separate the layers and extract the aqueous layer with one portion of ethyl acetate (100 mL). Combine the organic extracts, dry over sodium sulfate, and concentrate in vacuo. Triturate the crude oil with hexane/ether to give 36 g of the title compound. Concentrate the filtrate. Chromatograph the residue on silica gel (elute with 10:9:1 CH2Cl2, ether, MeOH). Precipitate the purified product from ether/hexane to give 21 g of the title compound. Combined yield: 57 g (76%) of title compound as a yellow crystalline solid. MS ES+ m/e 249.0 (M+1).