Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C1C=CC2OC(=O)CCC=2C=1.O1C2C(=CC=CC=2)C=CC1=O.[Cl:35][S:36](O)(=[O:38])=[O:37].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:36]([Cl:35])(=[O:38])=[O:37])[CH:8]=2)[O:3]1
Reactant: O=S(=O)(O)Cl
Reactant: CC1(C)C=Cc2ccccc2O1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C1CCc2ccccc2O1
Agent: O=c1ccc2ccccc2o1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 5 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 2,2-dimethylchroman [obtained by an analogous procedure to that described in Chem. Ber., 1904, 37, 494, for the preparation of 2,2-dimethyl-2H-chromene, but using dihydrocoumarin as starting material in place of coumarin] (50 g, 308 mM) in dichloromethane (250 ml) was added dropwise to a solution of chlorosulphonic acid (40 ml, 602 mM) and phosphorus pentachloride (50 g, 204 mM) in dichloromethane (250 ml), cooled to 5° C. under an atmosphere of argon. The colour of the solution changed from pale yellow to orange. When the addition was complete, the mixture was slowly allowed to attain ambient temperature and stirred for 2 hours. The reaction mixture was poured onto ice-water and the organic phase was separated. The aqueous layer was extracted with dichloromethane (3×20 ml), and the combined organic extracts were washed with water and dried (MgSO4). The solvent was removed by evaporation to give 2,2-dimethylchroman-6-sulphonyl chloride as a pale purple solid (42.6 g, 53% yield), m.p. 89°-92° C. (after recrystallisation from hexane).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15](O)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][N:7]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(COC)OC.O>[NH:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:25]=[C:15]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1
Reactant: Nc1ccccc1N
Reactant: Nc1ncc(-c2cccc(F)c2)nc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Nc1ncc(-c2cccc(F)c2)nc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
3-amino-6-(3-fluorophenyl)pyrazine-2-carboxylic acid (0.096 g, 0.41 mmol), ortho-phenylenediamine (0.049 g, 0.45 mmol), diethyl cyanophosphonate (0.07 g, 0.45 mmol), and triethylamine (0.083 g, 0.82 mmol) were combined in 5 mL of dimethoxyethane. The mixture was heated to 200° C. for 10 min in the SmithSynthesizer microwave. The cooled mixture was poured into 30 mL of H2O and the mixture was filtered to collect 3-(1H-benzimidazol-2-yl)-5-(3-fluorophenyl)pyrazin-2-amine (23 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[O:5][C:4](=[O:18])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][C:4](=[O:18])[CH2:3]1
Reactant: CC1(C)CC(=O)Oc2ccc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CC(=O)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.15 g (8.0 mmol) of 4,4-dimethyl-6-trimethylsilylethynyl-2-oxo-chroman in 25 ml of methanol was added, under nitrogen, 1.0 g of potassium carbonate. The reaction mixture was stirred at room temperature for 12 hours and the methanol was then removed under vacuum. The residue was extracted with methylene chloride (2×15 ml) and the combined organic layers were washed with dilute HCl, water, brine and dried (MgSO4). The solvent was removed in-vacuo and the residue purified by Kugelrohr distillation to give the title compound as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.Cl[C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([NH:13][C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:11][CH2:12]1
Reactant: COC(=O)CCC(=O)Cl
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (3.50 g) in dichloromethane (100 ml) was added methyl 4-chloro-4-oxobutanoate (2.00 g) dropwise. Triethlamine (3.90 g) was added and the reaction stirred under nitrogen for 2 hours. Saturated sodium hydrogen carbonate solution was then added, with the solution being extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over anhydrous magnesium sulfate. After filtration the solvent was removed under reduced pressure to leave methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][S:9]1(=[O:15])=[O:14].[Mn]([O-])(=O)(=O)=[O:18].[K+].[OH-:23].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][S:9]1(=[O:15])=[O:14])[C:16]([OH:18])=[O:23]
Reactant: Cc1ccc(N2CCCCS2(=O)=O)c(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(N2CCCCS2(=O)=O)c(Cl)c1

Procedure:
250 mg (0.96 mmol) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-toluene are suspended in 10 ml of water and combined with 456 mg (2.89 mmol) potassium permanganate and 39 mg (0.98 mmol) sodium hydroxide. The reaction mixture is refluxed for 4 hours. After cooling to ambient temperature sodium thiosulphate is added to decolorise the mixture which is then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol=19:1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:24]1C=CC=CC=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:24]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1ccccc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using aniline instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.19 (s, 3H), 4.48 (d, J=5.8 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 6.95 (bs, 1H), 7.11 (bs, 2H), 7.20 (t, J=6.2 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.52 (bs, 2H), 7.69 (t, J=6.9 Hz, 1H), 7.90 (s, 1H), 8.51 (d, J=4.3 Hz, 1H); MS (ESI) m/z 306.1 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([OH:18])=[O:17].C([BH3-])#N.[Na+]>C(O)C.O>[C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5])[CH3:3])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:18])=[O:17]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(N)=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
Couple L-alanyl-L-proline amide, prepared as in Example 51, with 2-oxo-4-phenylbutyric acid employing sodium cyanoborohydride in 50% ethanol-water by the method described in example 2. After eluting from the ion-exchange resin, concentrate in vacuo to a small volume, flush with water, and freeze-dry to obtain N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline amide as a mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6]Cl)[CH2:2][Cl:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[Cl-:3].[CH2:2]1[N+:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:1]1
Reactant: ClCCOCCCl
Reactant: C1COCCN1
Product: C1C[N+]2(CCO1)CCOCC2
Product: [Cl-]

Procedure:
In a preferred embodiment, 2,2'-dichlorodiethylether was reacted with morpholine to form 3,9-dioxa-6-azoniaspiro [5.5] undecane chloride as the intermediate.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2ccc(C(F)(F)F)cc2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][OH:43]>C(O)=O.[Fe]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH:42]=[O:43])=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: [Fe]
Solvent: O=CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(NC=O)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-benzyloxycarbonylamino-2-(4-nitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (2.02 g) in 90% aqueous formic acid (56 mL) was added iron powder (3.9 g). The mixture was stirred at room temperature overnight. Methanol was added and the reaction mixture filtered through diatomaceous earth to remove the excess iron. Ethyl acetate was added and the resultant solution washed with water (twice), brine, then dried (MgSO4) and evaporated. The crude material was purified by chromatography, with dichloromethane:methanol (gradient, 99.5:0.5, 98.2) as the eluent, followed by trituration with hexane:diethyl ether (80:20), to provide the title compound (1.12 g) as an off-white solid; TLC: Rf =0.39, dichloromethane:acetone (70:30); NMR: 0.67-1.03 (m,6), 2.03-2.33 (m,1), 4.00-4.80 (m,3), 5.17 (s,2), 7.20-7.60 (m,7), 7.57-7.77 (m,2), 8.22 (s,1), 8.43 (s,1), 8.83- 9.07 (m,2), 10.30-10.57 (m,1); MS: m/z=574(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1.N1CCCCC1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1
Reactant: BrCC1CO1
Reactant: O=C1C=C(c2ccccc2O)CC1
Solvent: C1CCNCC1
Product: O=C1C=C(c2ccccc2OCC2CO2)CC1

Procedure:
2.0 g 3-(2-hydroxyphenyl)-2-cyclopenten-1-one are stirred with 30 ml epibromohydrin and catalytic amounts of piperidine for 1 hour at 100° C. After concentration, the mixture of epoxy- and bromohydrin is separated by high-pressure liquid chromatography. In this manner, 2 g 3-[2-(2,3-epoxypropoxy)-phenyl]-2-cyclopenten-1-one are obtained as an oil which is then dissolved in 20 ml t-butanol. 2 ml of t-butylamine were added and the mixture is stirred at room temperature for 48 hours.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:37])=[C:14]([C:30]([O:32]C(C)(C)C)=[O:31])[CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:10][C:11]1[NH:12][C:13]2[CH2:37][O:32][C:30](=[O:31])[C:14]=2[CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: CC1=C(C(=O)OC(C)(C)C)C(c2ccccc2)C(C(=O)OC(C)(C)C)=C(C)N1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)OC(C)(C)C)C(c2ccccc2)C2=C(COC2=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
In a manner similar to that previously described, 1.14 gram of 80 percent pyridinium bromide perbromide (2.85 millimoles) was added to a cooled to 0° C. solution of 1.00 gram (2.59 millimoles) of di-t-butyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.81 milliliter of pyridine in 20 milliliters of dry chloroform. The resulting mixture was stirred for 30 minutes at 0° C. and then heated at reflux for 90 minutes. Thereafter, the mixture was cooled to room temperature, diluted with 200 milliliters of ethyl acetate and washed successively with 5 percent hydrochloric acid and brine, dried over magnesium sulfate, then filtered to remove the drying agent and the filtrate subjected to reduced pressure to vaporize the solvent and recover 0.90 gram of product as a yellow oil. The oil was chromatographed on 50 grams of silica gel using 1:1 ethyl acetate-hexane as eluant to obtain 250 milligrams (29 percent yield) of white crystalline t-butyl 2-methyl-4 -phenyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product which after recrystallization from diethyl ether and drying at 70° C./0.05 millimeters Hg pressure for 48 hours and 100° C./0.005 millimeters Hg for 24 hours had a melting point of 185°-188° C. Elemental analyses for the product were as follows:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.ClC([O:16][CH2:17][CH:18]([CH3:20])C)=O.[NH2:21][C@@H](C(O)=O)CC1N=CNC=1>>[C:20]([CH2:18][C:17]([NH:2][C@@H:3]([CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)[C:10]([OH:12])=[O:11])=[O:16])#[N:21]
Reactant: CC(C)COC(=O)Cl
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Product: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
An optical purity of >99.8% was determined for a sample obtained according to the procedure above. The determination was carried out by hydrolysing the amide bond (6 N hydrochloric acid, 110° C., 24 h), followed by derivatizing the liberated histidine with trifluoroactetic anhydride and isobutyl chloroformate. A D-histidine content of <0.1% was detected by means of gas chromatography on a chiral stationary phase.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1>>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2ccccc2)[nH]n1
Reactant: OCc1ccc(CCl)cc1
Product: CC(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Yield: 9 %

Procedure:
In the same manner as in Reference Example 41, the title compound (285 mg, yield 9%) was obtained as a colorless oil from 3-isopropyl-5-phenyl-1H-pyrazole and [4-(chloromethyl)phenyl]methanol. 1H NMR (CDCl3) δ: 1.32 (6H, d, J=7.0 Hz), 1.64 (1H, t, J=5.8 Hz), 2.99-3.09 (1H, m), 4.66 (2H, d, J=5.8 Hz), 5.30 (2H, s), 6.18 (1H, s), 6.97-7.06 (2H, m), 7.24-7.39 (7H, m).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].[CH3:5][S:6][CH3:7].[F:8][B-:9]([F:12])([F:11])[F:10].[H+]>>[F:8][B-:9]([F:12])([F:11])[F:10].[CH2:1]([S+:6]([CH3:7])[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: CSC
Agent: F[B-](F)(F)F
Agent: [H+]
Product: C=CC[S+](C)C
Reaction time: 144 h

Procedure:
Into a 3-neck 5-liter flask were weighed 1161.6 g (20 moles) of allyl alcohol, 950 g (15.3 moles) of dimethyl sulfide, and 1829 g (10 moles) of 48% aqueous tetrafluoroboric acid. The flask was attached to a large (1.5 liter) capacity Dean-Stark trap (initially filled with dimethyl sulfide) which was attached to a condenser. Reflux was started and an aqueous phase began to accumulate at the bottom of the Dean-Stark trap, displacing dimethyl sulfide back into the reaction mixture. Reflux was continued for six days. At the end of this period, the rate of accumulation of aqueous phase had become very small. The aqueous phase was drained into a tared bottle and weighed; the net weight of the aqueous phase was 1136.7 g. Excess dimethyl sulfide and allyl alcohol were allowed to distill at atmospheric pressure into the Dean-Stark trap until the temperature in the flask had reached 100° C. At this point, the flask was connected to a dry ice trap and vacuum was applied. The mixture in the flask was evaporated at 70° C. under magnetic stirring for one hour, with the pressure decreasing to a final value of 200 Pa. The yield of nonvolatile product was 1952 g. The nonvolatile product was a viscous liquid containing a small amount of crystals. It showed no signs of further crystallization on standing at room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and methyl bromoacetate (16 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 100° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 followed by trituration with diethyl ether afforded 10 mg (26%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole: 1H. NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.92 (t, 1H), 7.50 (t, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Cl:23]
Reactant: COc1ccc(CO)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzyl alcohol (1 g, 6.5 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (1.8 mL, 13 mmol) and methanesulfonyl chloride (0.60 mL, 7 mmol) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.1 g, 100%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])[C:18]([CH:11]1[C:10](=[O:21])[C@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (3.9 mL; 28 mmol) was added over a period of 2-3 min to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 2.2 g, 10.2 mmol) in dichloromethane (25 mL), resulting in a heavy precipitate. Dichloromethane (10 mL) was added, followed by N′-(2-chloro-4-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 33; 1.87 g, 7.2 mmol). The reaction mixture was stirred at 0° C. for 5 min, and then at 50° C. (oil-bath temperature) over the weekend. Dichloromethane was added and the solution was washed with water (3×50 mL) and brine (50 mL), dried (magnesium sulfate, filtered, evaporated, and dried under high vacuum to give N′-(2-chloro-4-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (3.8 g, 120% of the expected amount). This was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:24]([NH:26][C:27](=[O:44])[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:25].C(=O)([O-])O.[Na+].C(Cl)Cl>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:24]([NH:26][C:27]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:29]=1)=[O:44])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3cc(Br)ccc23)CC1
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(N4CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Yield: 82.2 %

Procedure:
A mixture, of 1,1-dimethylethyl 4-(6-bromo-1H-indazol-3-yl)-1-piperazinecarboxylate (Intermediate 6, 660 mg) N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 598 mg) tetrakis(triphenylphosphine)palladium (25 mg) and aqueous sodium hydrogen carbonate (1M, 1.5 ml) in isopropanol (6 ml) was stirred at 150° C. for 20 min in a microwave oven. DCM and water were added and the organic phase was separated using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by chromatography on a silica column eluting with a cyclohexane/ethyl acetate gradient to give the title compound (660 mg).