Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[O:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:6]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of (RS)-tert-butoxycarbonylamino-(3-hydroxy-phenyl)-acetic acid methyl ester (CAS 526217-60-7) in THF (10 ml) was treated under an argon atmosphere with tetrahydro-pyran-4-ol (0.24 ml), triphenylphosphine (649 mg) and di-tert-butyl azodicarboxylate (570 mg) and stirred at r.t. overnight. The reaction mixture was concentrated. The crude product was purified by column chromatography (silical gel; gradient: cyclohexane ->cyclohexane/EtOAc 1:1) to give (RS)-tert-butoxycarbonylamino-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid methyl ester (884 mg, 82%) as viscous light yellow oil.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].O=[C:6]=[CH2:7].O=C=C.C(#N)C=C.[CH:15]([O:17][C:18]([CH3:21])(C)C)=[CH2:16].N(C(C)(C)C#N)=NC(C)(C)C#N>CS(C)=O>[C:1](#[N:4])[CH:2]=[CH2:3].[CH2:18]([O:17][CH:15]=[CH2:16])[CH2:21][CH2:6][CH3:7]
Reactant: C=COC(C)(C)C
Reactant: C=C=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CS(C)=O
Solvent: C=CC#N
Product: C=COCCCC

Procedure:
A copolymer of acrylonitrile/oxoethylene containing 121/2 moles of oxoethylene per 100 moles of acrylonitrile was prepared by (a) copolymerising a mixture of acrylonitrile and tertiarybutyl vinyl ether dissolved in dimethyl sulphoxide solvent using azobisisobutyronitrile as an initiator to form an acrylonitrile/butoxyethylene copolymer, (b) dissolving the copolymer in an aqueous solution of sodium thiocyanate and hydrolysing the tertiarybutoxy grouping with hydrobromic acid to form an acrylonitrilehydroxyethylene copolymer and (c) oxidising this copolymer with dimethyl sulphoxide/acetic anhydride to form the acrylonitrileoxoethylene copolymer. The experimental details are as follows:
Reaction SMILES: [BH4-].[Na+].B(OC)(OC)OC.[F:10][C:11]1[CH:30]=[CH:29][C:14]([C:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=2[C:26](O)=[O:27])=O)=[CH:13][CH:12]=1.O>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([CH:15]2[C:17]3[C:18](=[CH:19][C:20]([CH2:21][OH:22])=[CH:24][CH:25]=3)[CH2:26][O:27]2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 35 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a suspension of sodium borohydride (43.5 g) dispersed in THF (327 ml) was added trimethyl borate (9.1 g) and added dropwise at 20–30° C. a solution of 4-(4′-fluorobenzoyl)isophthalic acid (100.5 g) synthesized in Example 4 in THF (313 ml), and the mixture was heated to 35° C. A boron trifluoride-THF complex (181.7 g) was added dropwise at 35–42° C. After the dropwise addition, the mixture was heated at 40–50° C. for 7 hr, and hydrolyzed with water (101 ml) in an ice bath. THF was evaporated under reduced pressure. To the residue was added 30% sulfuric acid (110 g) and the mixture was stirred at 60° C. for 5 hr. A 25% aqueous solution of sodium hydroxide (200 g) was added and the mixture was extracted with hot toluene (450 ml) at 70° C. The hot toluene layer was washed with warm water (70° C., 60 ml), heptane (450 ml) was added and the mixture was cooled. The precipitated crystals were collected by filtration and dried to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (69.0 g, 81%). The various spectrum data of the crystals were the same as those obtained in Example 12.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[N:13][C:14]([NH2:26])=[C:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[C:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[C:14]([NH2:26])=[N:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester (0.225 g, 0.6 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (0.5 mL, 6 mmol), the mixture was stirred at RT for 2 h. Aq. satd. NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2/MeOH (10%, 4×30 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated at reduced pressure to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=3.78 (s, 2H), 7.42-7.58 (m, 2H), 7.88 (d, J=6.8 Hz, 1H), 8.05-8.07 (m, 2H), 8.32 (d, J=1.8 Hz, 1H). MS (ES+): m/z=281.14 (100) [MH+]. HPLC: tR=2.01 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCCOCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 272 mg of 8a in 3 ml of dioxane was mixed with 170 mg of KOH in 1.5 ml of water. The mixture was stirred for 1 h at 55° C. after which all starting material had disappeared, as judged by TLC analysis. The reaction mixture was cooled, diluted with 10 ml of water and acidified to pH3 by addition of cold 0.5N HCl. The product was extracted with ethyl acetate. The combined organic layers were washed once with water, dried and concentrated. The product 8b, 210 mg, thus obtained was used without further purification in the next step.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1.[C:9](OC)(=[O:13])[C:10]([CH3:12])=[CH2:11].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:9]([O:8][CH2:7][CH:1]1[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1)(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)OC
Reactant: OCC1C=CCC=C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCC1C=CCC=C1
Yield: 87 %

Procedure:
The method of Example 1 was substantially repeated with 2,5-cyclohexadienylmethanol (40.86 g, 0.37 mol, containing ca. 13% 2-cyclohexenylmethanol), methyl methacrylate (159 mL, 1.5 mol), phenothiazine (0.1 g), and tetraisopropyl titanate (2.0 mL). The excess methyl methacrylate was distilled at 70 mm and the product was distilled to give 57.5 g (87% yield) of clear, colorless liquid 2,5-cyclohexadienylmethyl methacrylate, bp 58° C./0.15 mm to 54° C./0.12 mm. IR (film): ν 3030, 2941, 1709, 1629, 1445, 1309, 1287, 1152, 1009, 979, 934, 873, 810 cm-1. 220 MHz 1H NMR: δ 6.07 (1H, m, methacrylate vinyl), 5.8 (2H, m, vinyl), 5.6 (2H, m, vinyl), 5.50 (1H, m, methacrylate vinyl), 4.04 (2H, d, J=6), 3.1 (1H, m, allylic methine), 2.6 (2H, M, allylic methylene), and 1.93 (3H, m, allylic CH3); the minor impurity of cyclohexenylmethyl methacrylate showed a broad envelope of signals from δ 2.0 to 1.3 and a 6 Hz doublet (--CH2O) at 4.02 which showed it to be 13% of the mixture. 22.63 MHz 13C NMR: δ 167.1, 137.7, 126.3, 125.4, 125.2, 68.0, 35.7, 26.5, 18.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11]/[CH:12]=[CH:13]\[F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C#CCF)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C/C=C\F)cc1
Yield: 99.3 %

Procedure:
Stir a mixture of 533 mg, 2.51 mmoles of the title compound of Example 1 (recrystallized from dichloromethane-hexane), 211 mg, 2.67 mmoles of pyridine and 127 mg of Lindlar catalyst (palladium on calcium carbonate, poisoned with lead (obtained from Aldrich) in 25 mL of ethyl acetate under hydrogen at atomospheric pressure at 26° C. for 1 hr until the theoretical amount of hydrogen (62 mL) is consumed. Remove the catalyst by filtration and wash it with ethyl acetate. Wash the ethyl acetate solution successively with ice-cold 4% HCl solution, saturated NaHCO3 solution and water, and dry over anhydrous MgSO4. Evaporate solvent under vacuum to give the title compound as an oil (534 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[CH:23][N:22]=3)[CH:17]([CH2:33][C:34](OC)=[O:35])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-:38].[Na+].O.Cl>O1CCCC1.CO.C(Cl)Cl.CO.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[CH:25][N:26]=3)[CH:17]([CH2:33][C:34]([N:15]3[CH2:20][CH2:19][O:38][CH2:17][CH2:16]3)=[O:35])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1c1ncc(-c2ccncc2)cn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1c1ncc(-c2ccncc2)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
In tetrahydrofuran (10 ml) and methanol (5.0 ml) was dissolved 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine (583 mg). Under ice cooling, a mixture of sodium hydroxide (200 mg) and water (1.0 ml) was added dropwise to the resulting solution under ice cooling, followed by stirring at room temperature for 5 hours. Under ice cooling, concentrated hydrochloric acid (420 μl) was added to the reaction mixture to make it weakly acidic. The reaction mixture was then distilled under reduced pressure. To the residue were added morpholine (102 μl), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (239 mg) and 1-hydroxybenzotriazole hydrate (159 mg). The resulting mixture was dissolved in N,N-dimethylformamide (60 ml) and methylene chloride (30 ml). Diisopropylethylamine (760 μl) was added dropwise to the resulting solution under ice cooling, followed by stirring at room temperature for 12.5 hours. The reaction mixture was distilled under reduced pressure. A 100% aqueous solution of citric acid was added to the residue and it was extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (10% methanol—methylene chloride) using as a carrier silica gel, followed by crystallization from methylene chloride-tetrahydrofuran, whereby a crudely purified product (349 mg) was obtained. A portion (161 mg) of then product was dissolved in methylene chloride-methanol. To the resulting solution was added 1N aqueous hydrochloride in ethanol (260 μl) and the mixture was concentrated to dryness. Ethyl acetate was added to the concentrate and the solid thus obtained was collected by filtration, washed with ethyl acetate and dried, whereby the title compound (117 mg) was obtained as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[F-:11].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:11])[C:5]#[N:6]
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(F)c(Cl)c1
Temperature: 170 °C
Yield: 92 %

Procedure:
172 g of 3,4-dichlorobenzonitrile, 200 g of dimethylsulfoxide, 69.6 g of potassium fluoride, and 3.95 g of (N,N-dimethylimidazolidino)tris-(diethylamino)phosphazenium chloride were placed in a 1 liter four-neck flask equipped with anchor stirrer, thermometer, and reflux condenser with bubble counter. The mixture was then heated with stirring to 170° C. and this temperature was maintained for 6 hours. The mixture was then cooled to room temperature, water was added to the reaction mixture in a volumetric ratio of 1:1, and the 3-chloro-4-fluorobenzonitrile that precipitated was isolated by filtration, washing, and drying. 3-Chloro-4-fluorobenzo-nitrile was obtained in a yield of 92% of theory.
Reaction SMILES: [C:1]([CH2:4][PH:5](=[O:7])[O-:6])(=O)[CH3:2].[Na+:8].[NH2:9][NH:10][C:11]([NH2:13])=[S:12]>C(O)C>[C:1](=[N:9][NH:10][C:11]([NH2:13])=[S:12])([CH2:4][PH:5](=[O:7])[O-:6])[CH3:2].[Na+:8]
Reactant: NNC(N)=S
Reactant: CC(=O)C[PH](=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C[PH](=O)[O-])=NNC(N)=S

Procedure:
A mixture of sodium acetylmethylphosphinate (3.5 g) and thiosemicarbazide (2.2 g) was stirred in ethanol (15 ml) for 4 days. The precipitated hydrazone was filtered off and dried (4.6 g). The n.m.r spectrum supports the required structure. The compound slowly decomposes above 125°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:18]3[N:23]=[C:22]([NH:24][C:25]4[C:26]([C:27](=[O:28])[NH:29][CH2:30][C:31]#[CH:32])=[CH:33][CH:34]=[CH:35][C:36]=4[F:37])[C:21]([Cl:38])=[CH:20][N:19]=3)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COC(=O)N1CCCOc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-prop-2-ynylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (128 mg, 64%). LCMS (m/e) 525 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.41 (s, 1H), 9.19 (s, 1H), 9.05-8.96 (m, 1H), 8.19 (s, 1H), 7.58-7.41 (m, 3H), 7.27 (s, 1H), 7.14-7.06 (m, 1H), 6.94 (d, 1H, J=8.7 Hz), 4.07-3.85 (m, 4H), 3.73-3.40 (m, 5H), 3.13-3.08 (m, 1H), 1.95-1.80 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:11][CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)C1CCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)CC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)CC1
Yield: 89.4 %

Procedure:
To a solution of Example 11B (60 mg, 0.136 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (89 mg, 1.36 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (50 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-8.03 (m, 3H), 7.66 (s, 1H), 7.46-7.61 (m, 2H), 5.97-6.16 (m, 1H), 4.02-4.22 (m, 2H), 3.65-3.95 (m, 3H), 2.82-3.04 (m, 2H), 1.68-2.69 (m, 13H), 1.12-1.29 (m, 3H). MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2-(2-methoxyethoxy)ethanol (200 mg, 1.67 mmol, 1 equiv.), triethylamine (232 μL, 1.67 mmol, 1.0 equiv.) and tosyl chloride (317 mg, 1.67 mmol, 1 equiv.) in methylene chloride (5 mL, 0.29 M) was stirred at room temperature for 50 hours. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (10 g, hexanes/EtOAc 9:1 to 1:1) to afford (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate as a colorless oil (260 mg, 457 mg theoretical, 56.9%). LC-MS m/z 275 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CN1CCOCC1.[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])=[O:20]>C(Cl)Cl>[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:24])=[O:20]
Reactant: NCC(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Two solutions were prepared before the peptide coupling. Solution A: H-Gly-OH (1.2 eq.) was dissolved in MSA (3.0 eq.) at maximum 60° C. The suspension was cooled down to 25° C., diluted with DCM and stirred for at least 8 hours before being cooled to −15° C. In solution B, the carboxylic function of the Z-Glp-Pro-OH was dissolved with DCM and NMM (1.05 eq.). The solution was cooled to −15° C. The carboxylic acid was activated with IBCF (1.05 eq.) and the silylated solution A was then added to the slurry. The slurry was stirred for at least 0.5 h and left to warm to 25° C. The mixture was quenched with water and the addition of a solution of KHSO4 under stirring precipitated the peptide. The solid was filtered and washed with water. After drying under vacuum, 80% of Z-Glp-Pro-Gly-OH was recovered.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1(=O)[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>>[C:12]([CH2:11][CH:10]=[C:9]1[C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[O:2][C:1]2[C:8]1=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=2)([OH:14])=[O:13]
Reactant: Oc1cccc(O)c1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CC=C1c2ccc(O)cc2Oc2cc(O)ccc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Resorcinol (33.0 g, 0.300 mol) and succinic anhydride (30.0 g, 0.300 mol) were placed in a round bottomed flask and purged with nitrogen. Methanesulfonic acid (150 mL) was added and the solution was stirred at 65° C. for 2 hours under an atmosphere of nitrogen. The reaction mixture was added dropwise to rapidly stirred, ice-cooled water (1 L) with simultaneous addition of 50% aqueous sodium hydroxide to maintain pH 2.5 +/0.5. The product which appeared as a granular precipitate was collected by filtration and rinsed with water (3×100 mL) then acetone (3×100 mL). The product was air-dried then vacuum-dried (vacuum oven) at 110° C. for 18 hours to afford a dark red powder (37.7 g, 88%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)N1C=CC(CO[Si](C)(C)C(C)(C)C)=CC1CCC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1CCC(C)(C)C
Reaction time: 3.5 h
Yield: 98.7 %

Procedure:
To a solution of methyl 4-((tert-butyldimethylsilyloxy)methyl)-2-(3,3-dimethylbutyl)-pyridine-1(2H)-carboxylate (3.63 g, 9.87 mmol) in ethyl acetate (60 mL) was platinum (IV) oxide (224 mg, 1 mmol) added. Hydrogenated at 6 bar in a Büchi hydrogenator for 3.5 h. The catalyst was filtered off and the filtrate evaporated to yield methyl 4-((tert-butyl-dimethylsilyloxy)methyl)-2-(3,3-dimethylbutyl)piperidine-1-carboxylate (3.62 g, 99%) as a colourless oil. MS m/z 372 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[O:19]1[C:23]2[CH:24]=[CH:25][C:26](B(O)O)=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:2]3[CH:3]=[C:4]([N:8]4[CH2:16][CH:15]5[CH2:17][N:11]6[CH2:12][CH:13]([CH2:18][CH:9]4[CH2:10]6)[CH2:14]5)[CH:5]=[N:6][CH:7]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1cc2c(cc1-c1cncc(N3CC4CC5CC3CN(C5)C4)c1)OCO2

Procedure:
The title compound was prepared from the product of Example 65A and 1,3-benzodioxol-5-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 350.0 (M+H)+, retention time 1.37 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1
Reactant: c1cn[nH]c1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.73 g, 4 mmol), pyrazole (0.408 g, 6 mmol), Cu2O (0.057 g, 0.4 mmol), salicylaldoxime (0.219 g, 1.6 mmol), and Cs2CO3 (2.60 g, 8 mmol) in CH3CN (8 mL) was refluxed for 6 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title, compound (0.370 g, 25% yield) as a white solid: mp 187-189° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.72 (3H, s), 3.93 (3H, s), 6.55 (1H, dd, J=1.5, 2.3 Hz), 7.60 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.77 (3H, m), 7.84 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=2.6 Hz). Anal. Calcd for C17H16FN5O4: C, 54.69; H, 4.32; N, 18.76. Found: C, 54.58; H, 4.40; N, 18.67.