Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][CH2:20]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[CH2:12]([O:19][CH2:20][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCOCc1ccccc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCn2cccn2)cc1
Reaction time: 96 h

Procedure:
To a solution of pyrazole (2.0 g, 29 mmol) in DMF (20 mL) is added potassium carbonate (12.4 g, 90 mmol) and benzyloxymethylchloride (4 mL, 32.3 mmol). The reaction is stirred for four days, then poured into water and extracted with EtOAc . The organic layer is washed with 1 N NaOH, dried over MgSO4 and concentrated. The residue is purified by column chromatography using EtOAc as eluent to afford the title compound as a light yellow oil: (M+1)+=189.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH2:9]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH2:23][CH2:24]Cl)[CH:15]=1)[CH2:10][CH2:11][CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:24][CH2:23][C:16]3[C:17](=[CH:21][CH:22]=[C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])[CH:15]=3)[C:18]2=[O:19])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCCCOc1ccc(C(=O)Cl)c(CCCl)c1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(Br)cc1)C2=O

Procedure:
According to Method A, 4-bromo-phenylamine was reacted with 4-butoxy-2-(2-chloroethyl)-benzoyl chloride. In this way the product was obtained with molecular weight 374.28 (C19H20BrNO2); MS (ESI): 374 (M+H+).
Reaction SMILES: C([O:4][C@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(O)(=O)C.NN>CN(C=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: NN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.5 %

Procedure:
In 80 ml of DMF was dissolved 5.18 g of α-D-glucose pentaacetate, and 2.37 g of hydrazine acetate was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain 4.0 g of α-D-glucopyranose-2,3,4,6-tetraacetate (yield: 87%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[BrH:10].O>C1C=CC=CC=1>[Br:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: Br
Reactant: OCCCCCCCO
Solvent: c1ccccc1
Solvent: O
Product: OCCCCCCCBr
Reaction time: 12 h
Yield: 62 %

Procedure:
Heptane-1,7-diol (36.0 g, 272 mmol; Alfa Aesar) and aq. 48% HBr (38 mL) were heated under reflux in benzene (400 mL) with water removal using a Dean-Stark apparatus. After 12 h, all volatiles were removed in vacuo and the residue was purified by SiO2 column chromatography using a gradient of 10-30% EtOAc/hexanes as eluent to give 7-bromoheptan-1-ol (26.22 g, 62%) as colorless oil. TLC: 50% EtOAc/hexanes, Rf≈0.4; 1H NMR (400 MHz, CDCl3) δ 3.61 (t, 2H, J=7.1 Hz), 3.39 (t, 2H, J=6.8 Hz), 1.80-1.88 (m, 2H), 1.52-1.58 (m, 2H), 1.30-1.46 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>OS([O-])(=O)=O.[K+]>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCNC1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: O=C(O)c1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
5-Chloro-2-nitro-benzoic acid (42.3 g) and homopiperizine (100 g, 4.8 eq.) were mixed without solvent and heated at 110° C. After 10 min, the mixture had melted into an orange, thick solution. After 45 min total reaction time, the mixture turned to a dark black-brown color and become very thick. At this time, the mixture was cooled to room temperature and diluted with 10% KHSO4 (wt/vol) aqueous solution (pH 4). This mixture was stirred at room temperature for ˜1 hour and then filtered. The solid was rinsed with a mixture of hexanes and diethyl ether, diethyl ether and then hexane. The solid was then dried under vacuum. This resulted in 40.8 g (73%) of a dark brown solid. The compound was carried on to the next step without further analysis or purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][CH:10]=[C:11]1[C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Oc1ccccc1S
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Product: CCOC(=O)C(=NOC)C1=CSc2ccccc2O1
Yield: 15.5 %

Procedure:
2-Mercaptophenol (3.5 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (6.2 g.) in a similar manner to that of Example A--(i) to give ethyl 2-(1,4-benzoxathiin-2-yl)-2-methoxyiminoacetate (syn isomer, 1.2 g.), pale yellow crystals, mp. 78° to 80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c(N)c1
Yield: 81.5 %

Procedure:
Commercially available 4-t-butyl phenol (30 g, 0.2 mole) was dissolved in 200 mL ethyl acetate in a 600-mL round-bottomed flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture was treated with nitric acid (13 mL, in 13 mL water) dropwise over 10 min and then a catalytic amount of NaNO2. After 45 min the reaction was washed with excess 1N HCl and the organic layer was dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) was dissolved in 100 mL ethyl acetate and placed into a Parr bottle with a teaspoon of 10% Pd/C. The mixture was placed on a hydrogenator under 50 psi hydrogen with agitation for 1 hr. The catalyst was filtered off through celite, and the ethyl acetate was stripped off under vacuum. The material crystallized with the addition of about 200 mL heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11]1[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[C:13]([Br:22])[C:12]=1[NH2:23])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[ClH:24]>>[ClH:24].[CH2:1]([N:3]([CH2:10][C:11]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[C:13]([Br:22])[C:12]=1[NH2:23])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(N)c(CN(CC)C2CCCCC2)c1
Agent: Cl
Product: CCN(Cc1cc(C(=O)O)cc(Br)c1N)C1CCCCC1

Procedure:
13 gm of N-ethyl-2-amino-3-bromo-5-carbethoxy-N-cyclohexyl-benzylamine were boiled with 100 ml of 6 N hydrochloric acid for 1 hour. Subsequently, the supernatant liquid was decanted from the oily phase which had formed at the bottom, and the solution was evaporated to dryness. The residue was recrystallized from methanol, yielding N-ethyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine hydrochloride, m.p. 227°-229°C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[Br:14]N1C(=O)CCC1=O.Cl>CN(C)C=O.CO>[Br:14][C:5]1[S:1][C:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(-c2cccs2)cc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(Br)s2)cc1
Reaction time: 2 h

Procedure:
In a two necked flask under argon, 0.75 g (3.98 mmol) of 4-(2-thienyl)benzaldehyde in 20 mL of dimethylformamide (DMF) are cooled to 0° C. 1.1 eq. (0.78 g, 4.38 mmol) of N-bromosuccinimide (NBS) are solubilised in a mixture of 10 mL of DMF and 10 mL of methanol. This solution of NBS (protected from light) is then added drop by drop (30 min) to the reaction medium. The temperature of the medium is then left to return to ambient temperature over 2 h. The medium is hydrolysed with a solution of 1 mol·L−1 HCl and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After filtration and evaporation to dryness, the reaction mixture is recrystallised with acetone.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21](=O)[CH3:22])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH:21]([NH2:30])[CH3:22])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-n2cnnc2)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-n1cnnc1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanone (44 mg, 0.13 mmol), ammonium acetate (103 mg, 1.33 mmol) and sodium cyanoborohydride (17 mg, 0.27 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (15 mg, 34%). LCMS calculated for C17H17ClFN4 (M+H)+: m/z=331.1. found: 331.1.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][CH:7]1[S:11](=[O:13])(=[O:12])[O:10][CH2:9][CH2:8]1>O1CCCC1>[C:1]([NH:5][CH2:9][CH2:8][CH:7]([S:11]([OH:13])(=[O:12])=[O:10])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCOS1(=O)=O
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(CCNC(C)(C)C)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-butylamine (1.0 mL, 9.5 mmol) in tetrahydrofuran (15 mL) was added 2,4-butane sultone (1.33 g, 10.0 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with THF (2×20 mL), and dried in vacuo; affording compound ES: 1H NMR (DMSO, 500 MHz) δ ppm 2.97 (t, 2H, J=6.6 Hz), 2.62 (m, 1H), 1.95 (m, 0.5H), 1.750 (m, 0.5H), 1.22 (s, 9H), 1.12 (d, 3H, J=6.8 Hz). 13C NMR (DMSO, 125 MHz) δ ppm 56.17, 53.15, 29.87, 25.87, 17.05. ES-MS 207 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH3:10][O:11][C:12](=[O:16])[C:13](Cl)=[O:14].O>O1CCCC1>[CH3:10][O:11][C:12]([C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])=[O:14])=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cccc(CO)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.93 g of m-aminobenzyl alcohol in 50 ml of tetrahydrofuran was added dropwise a solution of 3.7 ml of chloroglyoxylic acid methyl ester in 20 ml of tetrahydrofuran, and this was stirred at room temperature for 1.5 hours. To the reaction solution was added water, and this was extracted with ethyl acetate, and washed with an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 5.10 g of 3-[(methoxycarbonyl)carbonylamino]benzyl alcohol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]([CH2:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of commercially available methyl 2-amino-5-bromobenzoate (10.0 g, 43.5 mmol) in dichloromethane (100 mL) was added 2-phenoxyacetyl chloride (6.60 mL, 47.8 mmol). The white suspension formed was cooled to 0° C. and treated with triethylamine (13.3 mL, 95.6 mmol) dropwise. The resulting solution was stirred at room temperature for 0.5 hours. The mixture was diluted with CH2Cl2 and was washed with water and saturated aqueous NH4Cl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 7% EtOAc-heptane), to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([C:50]([F:53])([F:52])[F:51])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:49][N:48]=[C:47]([C:50]([F:53])([F:52])[F:51])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1noc(CCl)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(C(F)(F)F)no3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole and isolated as brown gum. MS (m/e): 433.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:28]=1[O:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>>[F:43][C:40]1[CH:41]=[CH:42][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:24])=[C:28]([O:29][CH2:30][C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])[CH:39]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1OCC(=O)N1CCOCC1
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1OCC(=O)N1CCOCC1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 131, 2-(2-(aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.59 (6H, s, gem-Me), 3.38, 3.54 (4H, br, NCH2), 3.62 (4H, m, OCH2), 3.96 (2H, m, NCH2), 4.01 (2H, m, OCH2), 4.55 (2H, s, OCH2), 4.55 (2H, d, J=4.3 Hz, NCH2), 5.17 (2H, s, OCH2), 6.53 (1H, dd, J=10, 2.1 Hz, Ar—H), 6.63 (1H, dt, J=2.5, 8 Hz, Ar—H), 7.23–7.26 (1H, m, Ar—H), 7.28–7.30 (3H, m, Ar—Hs), 7.42–7.44 (2H, m, Ar—Hs), 8.00 (1H, t, J=5.5 Hz, NH); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 27.74, 38.76, 42.30, 42.98, 45.38, 58.06, 66.55, 66.78, 66.91, 74.72, 76.27, 100.40, 100.61, 108.07, 108.23, 122.56, 128.37, 128.49, 128.84, 130.88, 130.96, 139.69, 141.36, 141.98, 156.70, 157.02, 157.10, 159.58, 162.04, 163.99, 162.86, 165.79. HRMS (ESI) calcd for C30H34N4O7F (M+H) 581.2412. Found 581.2393.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]2[CH2:13][O:12]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>CCO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]2[CH2:15][OH:14])=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: COc1cc(C2CO2)ccc1C#N
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2CO)ccc1C#N
Temperature: 25 °C

Procedure:
A Pyrex vessel was charged with magnetic stirring bar, (2.0 g, 11.42 mmol) of 2-methoxy-4-(oxiran-2-yl)benzonitrile, (3.70 g, 17.12 mmol) of tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate, and 6 mL of EtOH. Then it was introduced in the microwave reactor and irradiated at 150° C. for 3 h. The mixture was cooled to room temperature and the solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, 1-20% dichloromethane/MeOH) which afforded the product as a mixture of two diastereomers (1:1) LC/MS: (IE, m/z) [(M+1)-t-Bu]+=336.41
Reaction SMILES: [O:1]=[O+][O-].CSC.[CH3:7][C:8]12[O:22][C@H:9]1[CH2:10][C@@H:11](/[C:14](/C)=[CH:15]\CC=C(C)C)[CH2:12][CH2:13]2>C(Cl)Cl>[CH3:7][C:8]12[O:22][CH:9]1[CH2:10][CH:11]([C:14](=[O:1])[CH3:15])[CH2:12][CH2:13]2
Reactant: O=[O+][O-]
Reactant: CC(C)=CC/C=C(/C)[C@H]1CCC2(C)O[C@H]2C1
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)C1CCC2(C)OC2C1

Procedure:
Compounds 8 and 9 were deoxygenated after the procedure of Delay and Ohloff, supra. These compounds dexoygenated (FIG. 1) individually or as a mixture, produced a single new compound that coeluted with 6 and matched the MS of synthetic 6. Isolated components in ca. 100 μl of CH2Cl2 were ozonized by addition of 100 μl of O3 -saturated CH2Cl2 at -78° C. (8341 Matheson Laboratory Ozonator), and ozonides were cleaved with methyl sulfide (30 μl; 40 μl/μl CH2Cl2). Compounds 12 and 13 (1-methyl-4-acetyl-1,2-epoxycyclohexane) were synthesized by standard methods and structurally verified by spectral comparisons to published values for these isomers. Ozonolysis of compounds 8 and 9 together produced ozonides 12 and 13 (FIG. 1) in approximately the same ratio as the ratio of 8:9 in airborne-trapped samples. Thus, compound 8 is trans-(Z)-1-methyl-4-(1,5-dimethyl-1,4-hexadienyl)-1,2-epoxycyclohexane. Deoxygenation of isolated 9 (>80% purity) produced a single compound having a GC-retention time and MS identical to synthetic 6 (FIG. 1). Ozonolysis of isolated 9 produced 13, but did not produce 12. Thus, component 9 is cis-(Z)-1-methyl-4-(1,5-dimethyl-1,4-hexadienyl)-1,2-epoxycyclohexane.
Reaction SMILES: [Br:1]Br.Cl.[C:4]1([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:16]1[S:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:13][C:12]=1[CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1sc(C2CCNCC2)nc1CCc1ccccc1
Reaction time: 0.5 h

Procedure:
At 0° C., bromine (123 mg) is added dropwise to a solution of 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 200 mg) in acetic acid (2 ml). The mixture is stirred for 30 min, and saturated sodium bicarbonate solution is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium carbonate, concentrated under reduced pressure and purified chromatographically. This gives 4-[5-bromo-4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine (127 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([CH3:14])=[CH:13][C:6]=12.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([CH3:14])=[CH:13][C:6]=12
Reactant: Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(Oc3ccc(N)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.9 %

Procedure:
A mixture of 4-(2-fluoro-4-nitrophenoxy)-2-methyl-1H-pyrrolo[2,3-b]pyridine (43 mg, 0. 15 mmol), zinc dust (50 mg, 0.75 mmol) and ammonium chloride (50 mg) in THF/Methanol (½, 0.6 mL) was stirred at room temperature for 1 h, filtered and concentrated in vacuo to afford the desired product (35 mg, 90%), which was sufficiently pure to use in the subsequent reaction. 1H NMR (DMSO-d6) δ 11.71 (s, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.10 (t, 1H, J=8.4 Hz), 6.64 (dd, 1H, J=10.4, 2.6 Hz), 6.51 (m, 1H), 6.35 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 5.50 (s 2H), 2.41 (s, 3H); MS(ESI+) m/z 258 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:32])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:12]1>>[CH3:9][N:10]([CH3:32])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([O:30][C:2]4[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=4)=[CH:28][CH:29]=3)=[CH:20][CH:21]=2)[CH2:12]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)C1
Reactant: Fc1ccc(Cl)nc1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Oc4ccc(F)cn4)cc3)cc2)C1

Procedure:
2-Chloro-5-fluoropyridine was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide by method R. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2
Reactant: OCc1cnc2ccc(Cl)cc2c1Cl
Reactant: O=S(Cl)Cl
Product: ClCc1cnc2ccc(Cl)cc2c1Cl
Reaction time: 24 h

Procedure:
11.4 g. of 4,6-dichloroquinoline-3-methanol (0.05 mol.) are added in portions to 150 ml. of thionyl chloride. The reaction mixture is allowed to stand for 24 hours at room temperature. Then the solution is filtered and the excess thionyl chloride removed by a rotary evaporator. The residue is triturated with water, filtered off, washed again with water and dried in a desiccator over P2O5 to obtain 3-chloromethyl-4,6-dichloroquinoline; yield: 11.5 g. (93.5%); m.p. 102°-105°. Recrystallization from cyclohexane does not change the melting point.
Reaction SMILES: [O:1]=[C:2]1C=C(C(O)=O)C=[CH:4][N:3]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].BrC1C=C(C=CC=1)O[C@H](C1[CH:44]=[CH:43][C:29]([C:30]([NH:32][CH2:33][C:34]2[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=2[CH3:40])=[O:31])=[CH:28][CH:27]=1)C>>[CH3:40][C:39]1[CH:38]=[C:37]([CH3:41])[NH:36][C:35](=[O:42])[C:34]=1[CH2:33][NH:32][C:30]([C:29]1[C:43]([CH3:44])=[CH:4][N:3]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:2](=[O:1])[C:28]=1[CH3:27])=[O:31]
Reactant: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3cccc(Br)c3)cc2)c(O)n1
Reactant: C[C@H](c1ccccc1)n1ccc(C(=O)O)cc1=O
Product: Cc1cc(C)c(CNC(=O)c2c(C)cn(C(C)c3ccccc3)c(=O)c2C)c(=O)[nH]1

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide (70 mg) were separated by SFC (Condition: Column: AS (250*30 mm, 5 um), eluent: CO2:EtOH:NH3.H2O=78:22:0.1, flow rate: 50 ml/min, column temperature: 38° C., wavelength: 220 nm) to give 15.6 mg and 14.8 mg of two enantiomers. The LCMS and HNMR of two enantiomers were the same as the racemic compound. Although the separated enantiomers were not optically characterized, for convenience sake the (R) enantiomer was designated Compound I-201 and the (S) enantiomer was designated Compound I-202.