Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:21][NH2:22].CN1CCCC1=O>O>[C:14]1([CH2:13][CH2:12][C:6]2[CH:5]=[CH:4][N:3]=[C:2]3[NH:21][N:22]=[C:8]([OH:9])[C:7]=23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: COC(=O)c1c(CCc2ccccc2)ccnc1Br
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1n[nH]c2nccc(CCc3ccccc3)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromo-3-methoxycarbonyl-4-(2-phenylethyl)pyridine (1.42 g), hydrazine monohydrate (0.65 mL) and N-methylpyrrolidone (10 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:31])[CH:9]=2)=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([N:32]4[CH2:37][CH2:36][CH2:35][C@@H:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]4)=[O:27])=[CH:29][CH:30]=3)[CH2:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:10]([CH3:31])[CH:9]=2)=[N:4][CH:3]=1
Reactant: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(Cl)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((1-(4-(5-chloropyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoic acid, ethyl (3R)-piperidine-3-carboxylate (6.40 mL), 1-hydroxybenzotriazole (5.61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.96 g) and diisopropylethylamine (7.25 mL) in dimethylformamide (60 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.88 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
120 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-aminophenyl)-2-oxoethyl]piperidine obtained in Example 64, 0.1 ml of triethylamine and 0.041 ml of methanesulfonyl chloride were dissolved in 2 ml of dichloromethane, and the mixture was stirred for 2 hours under ice-cooling. An aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 90 mg of the title compound as a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Yield: 99.1 %

Procedure:
Treatment of ((2R)-7-chloro-8-(2-chlorophenyl)chroman-2-yl)methyl 4-methylbenzenesulfonate (2.10 g, 4.53 mmol) with sodium azide (1.77 g, 27.20 mmol) in DMSO (50 mL) according to the procedure described for Example 69, Step 9 provided 1.5 g (99%) of (2R)-2-(azidomethyl)-7-chloro-8-(2-chlorophenyl)chroman as a white solid. MS (EI) m/z 333.0 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:19](=[O:21])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reaction time: 2 h
Yield: 292.1 %

Procedure:
A solution of 2-amino-5-bromo-benzoic acid (280 g, 1.3 mol) in acetonitrile (1.3 l) was warmed up to 50–55° C. Pyridine (206 g, 2.61 mol) and a solution of triphosgene (128.8 g, 0.43 mol) in dichloromethane (720 ml) were simultaneously added dropwise. After completion of the addition, the mixture was stirred at 50–55° C. for an additional 2 h. The solvent was removed under reduced pressure and water was added. The precipitate was collected by filtration, successively washed with water and chilled dichloromethane, and then dried under vacuum to afford the desired product 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (304 g, 98%). This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([O:19][CH2:20][CH2:21][CH2:22]CN(CCC)CCC)=[C:4](/[CH:8]=[CH:9]/[C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=[C:35](/[CH:52]=[CH:53]/[C:54]2O[C:56]3[CH:62]=[CH:61]C=C[C:57]=3[N:58]=2)C=C(OC)C=1OCCCN(CCC)CCC.CC1C=C(/C=C/C2OC3C=CC=CC=3N=2)C=C(C)C=1OCCCN(CCC)CCC>>[CH2:54]([N:58]([CH2:57][CH2:56][CH2:62][CH3:61])[CH2:22][CH2:21][CH2:20][O:19][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:8]=[CH:9]/[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:53][CH2:52][CH3:35]
Reactant: CCCN(CCC)CCCOc1c(OC)cc(/C=C/c2nc3ccccc3o2)cc1OC
Reactant: CCCN(CCC)CCCCOc1c(Cl)cccc1/C=C/c1nc2ccccc2o1
Agent: CCCN(CCC)CCCOc1c(C)cc(/C=C/c2nc3ccccc3o2)cc1C
Product: CCCCN(CCCC)CCCOc1ccccc1/C=C/c1nc2ccccc2o1

Procedure:
A compound of claim 1 selected from the group consisting of (E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole, (E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole and (E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole and acid addition salts thereof.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[F:21][C:22]([F:35])([F:34])[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)=[O:24]>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:31]([CH:28]3[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]([F:35])([F:21])[F:34])[CH2:30][CH2:29]3)=[O:32])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Product: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C1CCN(C(=O)C(F)(F)F)CC1

Procedure:
This compound was prepared according to the procedure of Example 35 using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(trifluoroacetyl)piperidine-4-carbonyl chloride as the starting materials. LCMS for C18H14BrF4N6O5 (M+H)+: m/z=549.0, 550.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[CH:3]=1.[N:22]([O-])=[O:23].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[C:3]=1[N:22]=[O:23]
Reactant: O=N[O-]
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2F)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a stirred solution of the product from example 4, step (c) (10 g) in acetic acid (300 ml) at room temperature was added a solution of sodium nitrite (2.24 g) in water (30 ml). The reaction was stirred at 0° C. for 30 min, and the resultant purple precipitate isolated by filtration, washing with water, to give the subtitled compound as a dark blue solid (4.8 g).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]1[CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19].[C:22]([C:25]1[CH:80]=[CH:79][C:28]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH2:59][O:60][C:61]3[C:62]([O:77][CH3:78])=[CH:63][C:64]4[C:70](=[O:71])[N:69]5[CH2:72][CH2:73][CH2:74][CH2:75][C@@H:68]5[CH:67]=[N:66][C:65]=4[CH:76]=3)[CH:36]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:38]=2)=[CH:27][CH:26]=1)(=O)[CH3:23]>C(Cl)Cl>[CH3:78][O:77][C:62]1[C:61]([O:60][CH2:59][C:35]2[CH:34]=[C:33]([CH:38]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:36]=2)[O:32][CH2:31][CH2:30][O:29][C:28]2[CH:79]=[CH:80][C:25](/[C:22](=[N:21]/[NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:10]3[C:9](=[O:8])[CH:13]=[CH:12][C:11]3=[O:14])/[CH3:23])=[CH:26][CH:27]=2)=[CH:76][C:65]2[N:66]=[CH:67][C@@H:68]3[CH2:75][CH2:74][CH2:73][CH2:72][N:69]3[C:70](=[O:71])[C:64]=2[CH:63]=1
Reactant: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@@H]3C=N4)cc(OCCOc3ccc(C(C)=O)cc3)c1)N=C[C@H]1CCCCN1C2=O
Reactant: NNC(=O)CCCN1C(=O)C=CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@H]3C=N4)cc(OCCOc3ccc(/C(C)=N/NC(=O)CCCN4C(=O)C=CC4=O)cc3)c1)N=C[C@@H]1CCCCN1C2=O
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide trifluoroacetic acid salt (246) (3 mg, 0.0096 mmol), (5Z,5′Z,6aR,6a′R)-3,3′-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one) (243) (7.5 mg, 0.0093 mmol) and 50 mg 4 Å molecular sieves was stirred in 2 ml of dry 5% HAc in DCM (one day earlier dried by 4 Å molecular sieves) for 2 h, neutralized with 0.5 ml of DIPEA, evaporated and purified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min and a gradient solvent system going from 80:20 solvent A:B at time 0-5 min to 50:50 A:B at 15 min then to 30:70 A:B at 25 min until to 10:90 A:B at 30 min. Solvent A—water, solvent B—methanol/dioxane (2:1)) and lyophilized to afford a white solid 5.6 mg (61%) of the title compound. MS m/z+1066.3 (M+2CH3OH+Na).
Reaction SMILES: Cl.[NH2:2][CH:3]([C@H:9]([CH2:17]C)[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CCN(C(C)C)C(C)C.[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O>C(Cl)Cl>[C:32]([O:31][C:29]([NH:2][CH:3]([C@H:9]([CH3:17])[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=CCCC(C)C[C@@H](CC)C(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A solution of (3R)-ethyl 2-amino-3-ethyl-5-methylnon-8-enoate hydrochloride (2.99 g, 10.77 mmole) in DCM (20 mL) was added DIPEA (1.08 mL, 10.77 mmole) followed by (BOC)2O (2.39 mL, 10.77 mmole) at room temperature. The reaction mass was stirred at room temperature for overnight. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by column chromotography (Silica gel, 20% ethyl acetate in pet-ether) to get 2.3 g, (62.5%) of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate as an oily liquid. MS: MS m/z 342.4 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[C:18]1([C:24](=[N:31][C:32]2[CH:33]=[N:34][CH:35]=[C:36]([CH:39]=2)[CH:37]=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:3]2[C:10]([CH:37]([C:36]3[CH:35]=[N:34][CH:33]=[C:32]([N:31]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:39]=3)[OH:38])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Reactant: O=Cc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cc(C(O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Reaction time: 0.83 h
Yield: 48 %

Procedure:
To stirred solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 226, 6.6 g, 22.7 mmol) in THF (130 mL) was added n-BuLi (18.2 mL of a 2.5M solution in hexane, 45 mmol) at −75° C. under N2, and the mixture was stirred for 50 min. A solution of 5-((diphenylmethylene)amino)nicotinaldehyde (Preparation 106, 6.5 g, 22.7 mmol) in dry THF (50 mL) was added and the mixture was stirred at −70° C. for 80 min. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc (300 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown solid in 48% yield, 5.2 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39]C(=O)C)=[CH:35][CH:34]=1.[C-:43]#[N:44].[Na+].O>CN1CCCC1=O.[Ni](Br)Br>[C:43]([C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)#[N:44]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(O)cc1
Temperature: 220 °C
Reaction time: 3 h

Procedure:
A mixture of 200 mg 1-chloro-2-(4-acetoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene, 35 mg sodium cyanide and 75 mg nickel bromide in 0.5 mL N-methyl-2-pyrrolidinone is heated in a microwave oven at 220° C. for 15 min. After cooling to room temperature, water is added and the resultant mixture is extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent, the residue is dissolved in 3 mL methanol. 3 mL of 4 M aqueous potassium hydroxide solution is added and the reaction solution is stirred at ambient temperature for 3 h. The solution is neutralized with 1 M hydrochloric acid and the methanol is evaporated. The residue is extracted with ethylacetate, the combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by HPLC on reversed phase (YMC C18; water/acetonitrile 95:5->1:99).
Reaction SMILES: CC1SC=C([C:7]#[C:8][C@:9]23[CH2:16][C@:13]([NH:17][C:18](C4C=NC=CN=4)=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)N=1.[CH3:26][C:27]1[S:28][CH:29]=[C:30](C#C[C@@]23C[C@@](NC(C4C=NC=CN=4)=O)(CC2)CCC3)[N:31]=1.[N:51]1[CH:56]=[CH:55][N:54]=[CH:53][C:52]=1C(O)=O>>[CH3:26][C:27]1[S:28][CH:29]=[C:30]([C:18]([NH:17][C@@:13]23[CH2:16][C@@:9]([C:8]#[C:7][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][N:51]=4)([CH2:15][CH2:14]2)[CH2:10][CH2:11][CH2:12]3)=[O:19])[N:31]=1
Reactant: Cc1nc(C#C[C@@]23CCC[C@@](NC(=O)c4cnccn4)(CC2)C3)cs1
Reactant: O=C(O)c1cnccn1
Reactant: Cc1nc(C#C[C@]23CCC[C@](NC(=O)c4cnccn4)(CC2)C3)cs1
Product: Cc1nc(C(=O)N[C@]23CCC[C@](C#Cc4cnccn4)(CC2)C3)cs1

Procedure:
Examples 52 and 53 of table 1, N-((1R,5S)-5-((2-methylthiazol-4-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide and N-((1S,5R)-5-((2-methylthiazol-4-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide, were prepared analogously to Example 14 from commerically available pyrazine-2-carboxylic acid and intermediate 7-A or 7-B at ˜0.1 mmol reaction scale, respectively. 1H NMR (500 MHz, CDCl3): δ 9.38 (d, J=1.4 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.50 (m, 1H), 7.90 (s, 1H), 7.18 (s, 1H), 2.69 (s, 3H), 2.49 (m, 1H), 2.29-2.13 (m, 3H), 2.02 (m, 2H), 1.91 (d, J=8.4 Hz, 1H), 1.86-1.71 (m, 5H); ESI-MS m/z: 353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=O>>[NH2:13][C:14]1[CH:15]=[C:16]([C:17]2[O:12][C:3]3[CH:4]=[C:5]4[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:11][C:2]=3[N:1]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1cc2ccccc2cc1O
Product: Nc1cccc(-c2nc3cc4ccccc4cc3o2)c1

Procedure:
Prepared by the method of Example 1a), from 3-amino-2-naphthol (579 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 58 mg (6%). 1H NMR (CDCl3) δ 8.12(s, 1H), 7.90(m, 3H), 7.65(dt, J=1.5, 7.5 Hz, 1H), 7.60(t, J=2.3 Hz, 1H), 7.42(m, 2H), 7.27(t, J=7.9 Hz), 6.82(dd, J=2.3, 7.9 Hz). MS 261 m/z (M+H)+.
Reaction SMILES: S[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]=1.[Cl:12]C(Cl)(SCl)C(Cl)Cl>COCCOC>[ClH:12].[OH:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]=[CH:2][N:7]=1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: CCCc1cc(O)nc(S)n1
Solvent: COCCOC
Product: CCCc1cc(O)ncn1
Product: Cl

Procedure:
To a slurry of 5.0 g (0.029 mol) of 2-mercapto-4-hydroxy-6-propyl pyrimidine in 50 ml of 1,2-dimethoxyethane was added 6.9 g (0.029 mol) of 1,1,2,2-tetrachloroethylsulfenyl chloride. The resulting mixture was heated at the reflux temperature for 10 minutes, and then filtered while still hot. The solvent was removed by evaporation under reduced pressure to give 8.8 g of 1,1,2,2-tetrachloroethylsulfenylmercapto)-4-hydroxy-6-propyl pyrimidine hydrochloride having a melting point of 142°-144° C. Analysis was as follows: %Cl, calc., 43.8, found 43.0; %S, calc. 15.8, found 15.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.1 %

Procedure:
673 mg (corresponding to 2.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine was dissolved in 25 mL of N,N-dimethylformamide, and 831 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. 275 μL (corresponding to 3.0 mmol) of 1-bromo-3-fluoropropane was added to the resulting solution, and the solution was stirred for 24 hours at room temperature. After the completion of the reaction, the reaction solution was poured into water, and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform), and further purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 349 mg (corresponding to 0.881 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 5, Step 3).
Reaction SMILES: [F:1][S:2]([C:5]([C:8]([C:11]([C:14]([F:16])=[O:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[F-:17].[K+].S(O[CH2:26][CH3:27])(OCC)(=O)=O.O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].COCCOCCOC>[F:1][S:2]([C:5]([C:8]([C:11]([C:14]([O:15][CH2:26][CH3:27])([F:17])[F:16])([F:12])[F:13])([F:9])[F:10])([F:7])[F:6])(=[O:4])=[O:3]
Reactant: [F-]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
In a procedure similar to that described in Preparation of Precursor 1, FSO2(CF2)3COF (70 g, 0.25 mole), KF (21.8 g, 0.37 mole), diglyme (350 ml), Adogen 464 (10.5 g of a 56% solution in anhydrous diglyme) and diethyl sulfate (48 g, 0.312 mole) were combined and reacted at 52° C. for 16 hours. Deionized water (˜250 g) was carefully added and the reaction mixture allowed to stir at about 65° C. for two hours. This was followed by heating the solution to about 105° C. and steam distilling the product into a Dean Stark trap after which the lower fluorochemical-containing phase was separated from the upper aqueous phase. The lower fluorochemical-containing phase mixture was distilled 51.3 g (147° C.) to yield FSO2(CF2)4OC2H5 (51.3 g); The product structure, which included three branched chain isomers, was confirmed by gc/ms, 1H and 19F NMR. FSO2(CF2)4OC2H5 (30.8 g, 0.094 mole) was treated with excess lithium hydroxide as described in Preparation 3 and converted to LiO3S(CF2)4OC2H5 (30.2 g). The product structure was confirmed by lc/ms and 1H and 19F NMR. A small impurity of CF3CFHOC4F8SO3Li was observed in the liquid chromatography/mass spectrometry (lc/ms).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:30])[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@:19]1([CH2:28][OH:29])[CH2:24][CH2:25][CH2:26][OH:27])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:30])[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@:19]1([CH:28]=[O:29])[CH2:24][CH2:25][CH:26]=[O:27])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@]1(CO)CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@]1(C=O)CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of dimethyl sulfoxide (16 g, 180 mmol) in dichloromethane (60 mL) was cooled to −78° C. in a cooling bath and treated dropwise with oxalyl chloride (14.2 g, 112 mmol). After the addition was complete, the solution was stirred for 30 minutes and then treated dropwise with a solution of [(1R,2S)-2-hydroxymethyl-2-(3-hydroxypropyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.8 g, 16.7 mol) in dichloromethane (100 mL). After the addition was complete, the solution was stirred for 40 minutes and then treated with triethylamine (19 g, 190 mmol). The mixture was stirred for 30 minutes. The cooling bath was removed and the mixture was allowed to warm to room temperature where it stirred for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL). The organic phase was removed, washed successively with water and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was removed under vacuum to give an oil (4.75 g). 1H NMR (300 MHz, CDCl3) δ9.78 (s, 1H), 9.41 (s, 1H), 4.56 (bd, J=9 Hz, 1H), 4.05 (m, 1H), 2.60-1.30 (m, 21H).