Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[CH3:10])[C:5]#[N:6].CC(N=NC(C#N)(C)C)(C#N)C.BrN1C(=O)CCC1=O.Cl.[C:33]([O:37][C:38](=[O:42])[CH2:39][NH:40][CH3:41])([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([CH2:10][N:40]([CH3:41])[CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])=[C:8]([F:11])[CH:7]=1)#[N:6]
Reactant: Cc1c(F)cc(C#N)cc1F
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C#N)cc1F
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 3,5-difluoro-4-methylbenzonitrile (1.53 g, 10 mmol) and AIBN (0.033 g; 0.20 mmol) in ACN (40 mL) was added N-bromo-succinimide (2.14 g, 12.0 mmol). The reaction mixture was heated at 90° C. for 24 hours. The solvent was evaporated in vacuo and the residue partitioned between water and DCM. The organic phase was passed through a hydrophobic frit and the solvent evaporated in vacuo. The residue was dissolved in CAN, and then sarcosine t-butyl ester hydrochloride (1.09 g, 6.0 mmol) and K2CO3 (2.07 g, 15 mmol) added. The reaction mixture was stirred at 70° C. for 18 hours. The suspension was filtered and the filtrate evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.22 (2H, d, J=5.9 Hz), 3.94 (2H, s), 3.21 (2H, s), 2.41 (3H, s), 1.48 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(Br)c3)nc2n(CC)c1=O
Yield: 47.2 %

Procedure:
Substantially the same procedure as in Reference Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.08 g (16.7 mmol) of 3-bromo-4-fluorocinnamic acid. The resulting crude crystals were recrystallized from dioxane to give 2.90 g (yield 47%) of Compound k as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18](C)=O.C[S-].[Na+].CCCCCCC>C(OCC)(=O)C>[CH3:17][S:18][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1CNc1cccc(Cl)n1
Reactant: CS(C)=O
Agent: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CSc1cccc(NCc2ccccc2O)n1
Temperature: 90 °C

Procedure:
Introduced into a microwave tube are 300 mg (1.28 mmol) of 2-[(6-chloropyridin-2-ylamino)methyl]phenol, to which 5 ml of dimethyl sulphoxide and 448 mg (6.4 mmol, 5 eq) of sodium methanethiolate are added. The reaction mixture is heated for 16 h at 90° C. The reaction medium is diluted with 50 ml of ethyl acetate and then washed with 50 ml of a saturated ammonium chloride solution then 2×50 ml of distilled water. The organic phase is dried over magnesium sulphate then filtered and concentrated to dryness. The residue is purified by chromatography over 40 g of silica with, as eluent, heptane/ethyl acetate (7/3). The product obtained is put back into solution in ethyl acetate, heptane is added until the solution becomes cloudy, it is then cooled to 0° C. and filtered. 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:14](=[O:19])[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:8][CH2:7]1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][S:5]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[C:14](=[O:19])[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:11]1)=[O:32]
Reactant: O=c1[nH]ccnc1CN1CCC(SCc2ccccc2F)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]ccnc1CN1CCC(S(=O)Cc2ccccc2F)CC1
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
After dissolving 57 mg of 3-[4-(2-fluorobenzylthio)piperidino]methyl-1H-pyrazin-2-one in 3 ml of dichloromethane, 31 mg of 3-chloroperbenzoic acid was added at below −70° C., the mixture was stirred for 30 minutes, and then an additional 5 mg of 3-chloroperbenzoic acid was added and the stirring was continued for 20 minutes. Aqueous sodium thiosulfate solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol/ammonia water) to obtain the title compound (16 mg, 27% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5,6-dichloronicotinate (2.0 g, 8.1 mmol)) in ethanol (40.3 mL) was added hydrazine hydrate (1.18 mL, 24.2 mmol). The mixture was heated 75° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was concentrated to dryness: LC-MS [M+1]=244.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])=O.[NH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[OH:11][C:5]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=1[CH2:2][CH:1]=[N:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NCC(=O)O
Solvent: O
Product: O=C(O)CN=CCc1ccc(O)cc1O

Procedure:
Ingredients. (1) Water 97.5 (2) Resacetophenone 1.5 (3) Glycine 1.0. Procedure. The mixture of all ingredients is heated at 90 to 95 C for 2 hours. A solution of N-[(2,4-Dihydroxyphenyl)ethylidene]glycine in water is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:16][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1
Reactant: [Li]CCCC
Reactant: COc1ccc(Br)c(C2OCCO2)c1
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(C)c(C2OCCO2)c1

Procedure:
A solution of 2-(2-bromo-5-methoxyphenyl)-1,3-dioxolane (5.44 g; 21 mmol; from step (i) above) in THF (dry, 60 mL) was cooled to −78° C. under a nitrogen atmosphere, and n-BuLi (1.4M; 19.5 mL) was added dropwise via syringe. After addition the solution was stirred at −78° C. for 35 minutes, whereafter MeI (13.41 g; 94.5 mmol) was added. The resultant mixture was slowly stirred to attain room temperature, and then quenched with NH4Cl/aq and extracted with ether. The organic phase was dried (Na2SO4) and concentrated, yielding 4.25 g (quantitative) of the sub-title compound as a brown oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:20]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(NC2CCC2)CCCCCC1.NC1SC=NC=1.C(OC(=O)CS)C>>[CH:16]1([N:15]([CH:20]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:27])=[O:3])=[CH:8][N:9]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCCC2)C2CCC2)s1
Agent: C1CCCC(NC2CCC2)CC1
Agent: CCOC(=O)CS
Agent: Nc1cncs1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCCC2)C2CCC2)s1

Procedure:
[2-(3-Cycloheptyl-3-cyclobutyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid ethyl ester prepared as described in general procedures (A) and (B) using cycloheptyl-cyclobutylamine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:24])=O>CN(C)C=O>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
To 9.4 g. (30 mmoles) of 2,5-di-(2,2,2-trifluoroethoxy)benzoic acid are added 2 drops of dimethylformamide and 7.2 ml. (11.9 g., 100 mmoles) of purified thionyl chloride. The product is refluxed for 3 hours and excess thionyl chloride is removed in vacuo (steam bath/water aspirator pressure). Last traces of thionyl chloride are removed by similar vacuum distillation with added benzene. The product is 2,5-di-(2,2,2-trifluoroethoxy)benzoyl chloride according to infrared spectral measurement.
Reaction SMILES: [ClH:1].C([N:5]1[CH2:20][CH2:19][CH2:18][C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([Cl:17])=[C:7]2[CH2:6]1)(=O)C.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:17].[ClH:1].[Cl:17][C:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][NH:5][CH2:6][C:7]=12
Reactant: CC(=O)N1CCCc2nc3ccccc3c(Cl)c2C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1c2c(nc3ccccc13)CCCNC2

Procedure:
11-Chloro-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline dihydrochloride was prepared by hydrolysis of 2-acetyl-11-chloro-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline hydrochloride with 2 N hydrochloric acid. Yield of the dihydrochloride: 11% of theory; m.p. 260° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[CH2:13]([N:15]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].C(O)(C)C>O>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][CH:17]([OH:20])[CH:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][CH:17]([OH:20])[CH:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14]
Reactant: CCN1CC2OC2C1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCN1CC(O)C(Oc2ccc(C(C)=O)cc2OC)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of acetovanillone and 1-ethyl-3,4-epoxypyrrolidine and 3 drops of water was heated on a steam bath overnight. The mixture was dissolved in 250 ml. of methylene chloride and extracted with three 150-ml. portions of 5% sodium hydroxide and one 100-ml. portion of water. The methylene chloride layer wad dried over anhydrous sodium sulfate and concentrated to give 19.0 g. crude oil. This oil was chromatographed on 400 g. of silica gel. The desired product was eluted with acetone. The fractions were concentrated to give 14.0 g. of oil which was treated with oxalic acid in isopropyl alcohol. The resulting white solid was recrystllized twice from isopropyl alcohol to yield 13.4 g. (24%) of sesquioxalate, m.p. 121°-3° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:26]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C)C=O>[C:18]([C:17]1[CH:21]=[CH:22][C:14]([C@@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:15][CH:16]=1)(=[O:19])[NH2:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(N)=O)cc2)C1
Reaction time: 6 h
Yield: 93.6 %

Procedure:
To a solution of 4-(2S)-4-(tert-butoxycarbonyl)morpholin-2-yl)benzoic acid (intermediate 16, 22.4 g, 72.9 mmol) in N,N-dimethylformamide (185 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.0 g, 109 mmol), 1-hydroxybenzotriazole hydrate (16.8 g, 109 mmol), N,N diisopropylethylamine (37.7 g, 292 mmol) and ammonium chloride (7.80 g, 146 mmol) at room temperature. After stirring for 6 hours the mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford (2S)-tert-butyl 2-(4-carbamoylphenyl)morpholine-4-carboxylate (intermediate 17, 20.9 g, 93%).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:17]1[C:29]([OH:31])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[NH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([C:50]#[N:51])=[CH:42][CH:41]=1>CCOC(C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[C@H:17]1[C:29](=[O:31])[NH:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([C:50]#[N:51])=[CH:42][CH:41]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)Nc1ccc(C#N)c2ccccc12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A solution of isobutylchloroformate (0.75 ml, 5.8 mmol) in dry EtOAc (8.0 ml) was cooled to −20° C., treated dropwise with a mixture of 30B (2.0 g, 5.8 mmol) and N-methylmorpholine (0.64 ml, 5.8 mmol) in dry EtOAc (6.0 ml) over a period of 45 minutes. The mixture was stirred at −20° C. for 30 minutes, then treated dropwise over a period of 1.5 h with a solution of 4-aminonaphthalene carbonitrile (976 mg, 5.8 mmol) in dry EtOAc (35 ml). The reaction mixture was stirred at −20° C. for an additional 3.0 h, then at RT for 4 days after which it was partitioned between water (50 ml) and EtOAc (3×250 ml). Purification by flash chromatography provided the title compound as a dark pink foam (2.19 g, 76.3%). MS (ES): m/z 496 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[C:14]([O:15]CC2C=CC=CC=2)=[CH:13][CH:12]=[C:11]([O:23][C:24]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[C:29]3[C:25]=2[CH2:26][CH2:27][CH2:28]3)[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.O.CSC>[C:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([O:23][C:24]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[C:29]3[C:25]=2[CH2:26][CH2:27][CH2:28]3)[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc(OCc2ccccc2)c1C(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CCOC(=O)c1c(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc(O)c1C(C)=O
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Ethyl 2-acetyl-3-benzyloxy-6-(5-methyl-7-nitroindan-4-yloxy)benzoate (314 mg) was dissolved in trifluoroacetic acid/water/dimethylsulfide (95/5/10) (3 mL). The mixture was stood overnight at room temperature and evaporated under reduced pressure to dryness. Adding water, the residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1−3/1) to give the title compound (217 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br)#[N:8].C(=O)([O-])[O-].[K+].[K+].[ClH:23]>C(O)C>[ClH:23].[C:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)#[N:8]
Reactant: N#Cc1ccccc1CBr
Reactant: C1=CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccccc1CN1CC=CCC1

Procedure:
1,2,3,6-Tetrahydropyridine (5.0 g.) was added to a mixture of 2-cyanobenzyl bromide (11.8 g.) and potassium carbonate (9.16 g.) in ethanol (80 ml.). The mixture obtained was heated under reflux for 2.5 hours, cooled and evaporated. Water (120 ml.) was added to the residue and the oily mixture obtained was extracted with ether (3×50 ml.). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue oil was dissolved in toluene (20 ml.) to give a solution, which was treated with a slight excess of methanolic hydrogen chloride. The mixture was evaporated and the solid residue which was left was triturated with acetone, collected by filtration, and recrystallised from a mixture of ethanol and ethyl acetate to give 1-(2-cyanobenzyl)-1,2,3,6-tetrahydropyridine hydrochloride, as colourless needles (7.1 g), m.p. 219°-221° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]2)[CH:3]=1.CC(O[K])=[O:26].O>CS(C)=O>[Cl:14][C:7]1[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([N:15]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]1)[CH:3]=[C:2]2[OH:26]
Reactant: CC(=O)O[K]
Reactant: COc1ccc2c(Cl)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 140 °C
Yield: 80 %

Procedure:
To a solution of compound 235a (250 mg) in DMSO (2.5 mL) was added CH3COOK (3 eq.), water (2 eq.). The reaction mixture was heated to 140° C. for 4 hrs. After cooled to RT, water (1 mL) was added to the reaction mixture slowly under stirring. Solid was filtered and washed with water to yield compound 236a in >80% yield. In a separate reaction, when 5 eq. of CH3COOK was used, the reaction was completed in 1 hr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[N+:6]([O-])=[N:7][C:8]=1[O:9][CH3:10].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>O>[C:13]([O:16][CH2:12][C:5]1[N:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: COc1cc(C)[n+]([O-])nc1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(COC(C)=O)nnc1OC

Procedure:
A mixture of 5,6-dimethoxy-3-methylpyridazine-2-oxide (0.5 g) in acetic anhydride (2 mL) is refluxed for 2 hours. After cooling the mixture is diluted with water and extracted with ethyl acetate (2×20 mL). The extracts are dried (MgSO4) and evaporated to give a brown oil which is purified by flash chromatography (ethyl acetate as eluent on silica) to give 6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) as a colourless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.I[C:32]1[N:36]([CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[N:36]([CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[N:35]=[CH:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Ic1ccnn1C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccnn2C2CCOCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 57.1 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (120 mg, 0.292 mmol), 5-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (97.4 mg, 0. 0.35 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.88 mL, 0.88 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (16.9 mg, 0.015 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give white solids, 72.6 mg (yield 57.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.59 (broad s, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.21 (d, J=1.1 Hz, 1H), 6.82 (broad s, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.78 (p, J=5.9 Hz, 1H), 4.51-4.34 (m, 1H), 3.98-3.84 (m, 2H), 3.73 (dddd, J=7.9, 3.9, 2.6, 0.6 Hz, 1H), 3.43-3.36 (m, 2H), 3.35 (m, 1H), 3.20-3.12 (m, 1H), 2.93-2.73 (m, 1H), 2.41-2.24 (m, 2H), 2.25-2.03 (m, 2H), 1.94-1.69 (m, 2H), 1.30 (d, J=5.9 Hz, 3H), 1.17-1.09 (m, 2H), 1.09-0.97 (m, 2H) ppm; MS (ESI+) m/z 436.16 (M+H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18].[F-:21].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+].C(O)C>CCCCCC.CCOCC.C(O)(=O)C>[F:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: [F-]
Reactant: COC(=O)CCSCCCCCCCCCCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CCSCCCCCCCCCCCCF
Yield: 34.2 %

Procedure:
Fluorination of 1 (0.2 g, 0.5 mmol) was performed by addition of tetrabutylammonium fluoride (TBAF) (4 mmol as 1M THF solution). The mixture was allowed to react at room temperature for 20 h. The resulting fluoro-ester was hydrolyzed by addition of 1 ml 1 N KOH and 1 ml ethanol for 2 h at room temperature. The product 2 (0.05 g, 34% yield) was isolated by column chromatography (hexane/ether/acetic acid 3:1:0.1) and recrystallized in hexane, TLC (hexane/ether/acetic acid 3:1:0.1) Rf=0.25. Melting point=59° C., 1H-NMR δ1.4 (m, 20H, CH2), 2.55 (t, 2H, C(2)H2), 2.65 (t, 2H, C(5)H2), 2.80 (t, 2H, C(3)H2), 4.44 (dt, 2H, C(16)H2JHH=6.2 Hz).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.068 g, 83%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.120 g, 0.26 mmol) and methylamine (1.24 g, 40.0 mmol). mp 147-149° C.