Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[N-:24]=[N+:25]=[N-:26].[Na+].[NH4+].[Cl-]>CCOCC>[N:24]([C@@H:17]1[CH2:16][O:15][C@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20][C@H:19]1[OH:18])=[N+:25]=[N-:26]
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A solution of (1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.05 g, 0.19 mmol) in a 8:1 MeOH/H2O (2 ml) mixture was treated with NaN3 (0.061 g, 0.94 mmol) and NH4Cl (0.022 g, 0.41 mmol) and the resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ether and the organic layer was separated. Evaporation of the washed (saturated aqueous NaHCO3, water) ether extracts afforded a crude solid product. Purification of the product by flash chromatography (Hexane/Ethyl Acetate=4:1) yielded (2S, 4R, 5R)-5-Azido-2-benzhydryl-tetrahydropyran-4-ol 30a 0.05 g (95%, [α]D=(−)109.3, c=1, MeOH).
Reaction SMILES: C1(S(CC[N:12]2[C:24]3[CH:23]=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)(=O)=O)C=CC=CC=1.[K].CC(C)([O-])C.C(OCC)(=O)C.Cl>O1CCCC1>[N+:25]([C:21]1[CH:22]=[CH:23][C:24]2[NH:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc2c(c1)c1ccccc1n2CCS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 g 9-(2-phenylsulphonyl-ethyl)-3-nitro-9H-carbazole are dissolved in 40 ml of tetrahydrofuran, combined with 700 mg potassium-tert.-butoxide and stirred for 2 hours at ambient temperature. A further 100 mg potassium-tert.-butoxide are added and the mixture is stirred for 4 hours at ambient temperature. Then another 100 mg potassium-tert.-butoxide are added. The mixture is heated for 2 hours to 50° C., divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is washed with saturated sodium chloride solution and dried with magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 80:20).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:12]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:33][C:32]=1[O:41][CH2:42][O:43][CH3:44])C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:44][O:43][CH2:42][O:41][C:32]1[CH:33]=[C:34]([O:37][CH2:38][O:39][CH3:40])[CH:35]=[CH:36][C:31]=1[C:12]1[N:11]([CH2:10][CH2:9][OH:8])[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]=1[CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCOCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCO)c2n1

Procedure:
To a solution of ethyl 1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (727 mg, 1.20 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 7.5% palladium carbon (225 mg), and the mixture was stirred at atmospheric pressure and in a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give ethyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate as a crude product. The obtained compound was used in Step 7 without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1.N1C(C)=CC(C)=CC=1C.[CH2:28]([S:35](Cl)(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:28]([S:35]([NH:1][C:2]1[C:3](=[O:18])[N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1)(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)c(N)cn(COC)c1=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(NS(=O)(=O)Cc2ccccc2)cn(COC)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of ethyl 5-amino-1-methoxymethyl-uracilylacetate (8.0 g, 31 mmole) and 2,4,6-collidine (13.7 mL, 62 mmole) in tetrahydrofuran (50 mL) is cooled in an ice bath. A solution of benzylsulfonyl chloride (5.93 g, 31 mmole) in tetrahydrofuran (50 mL) is added over a 30-minute period. After addition is complete, the solution is stirred for 1 hour at 0° C., then 3 hours at room temperature. The reaction mixture is diluted with ethyl acetate, washed with 1.0N HCl (until aqueous layer is pH 1), water, saturated sodium bicarbonate, and brine. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is removed. The title compound is isolated.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C[N+](C)(C)[CH2:16][C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2scc(C[N+](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
1-isopropenylbenzimidazolone (0.5 g, 2.9 mmol) in DMA (8 mL) was added and trimethyl-(4-methyl-benzo[b]thiophen-3-ylmethyl)-ammonium; iodide (1.0 g, 2.9 mmol) and K2CO3 (0.80 g, 5.74 mmol). The reaction mixture was heated to 120° C. for 15 min in a microwave and then 150° C. for another 5 min. The mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 0.7 g of the desired product as a white solid
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7])#[N:4].[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][N:13]=1.[CH3:19][N:20]([CH3:23])C=O>>[Br:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([CH:5]([C:3]#[N:4])[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])[CH:17]=1.[Br:11][C:12]1[CH:19]=[N:20][CH:23]=[CH:16][C:17]=1[CH:5]([C:3]#[N:4])[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]
Reactant: Brc1ccnc(Br)c1
Reactant: CN(C)C=O
Reactant: CN(C)C(=O)CC#N
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)C(C#N)c1cc(Br)ccn1
Product: CN(C)C(=O)C(C#N)c1ccncc1Br
Temperature: 60 °C

Procedure:
Sodium hydride (186.2 mg, 4.65 mmol, 60% dispersion in oil) was added to a solution of 2-cyano-N,N-dimethyl-acetamide (373.7 mg, 3.33 mmol) in dimethylformamide (10 mL) at 0° C. The mixture was removed from the ice bath for 20 min, and a solution of 2,4-dibromopyridine (300 mg, 1.33 mmol) in dimethylformamide (3 mL) was quickly added. The mixture was heated at 60° C. for 16 h. The reaction was cooled to room temperature, quenched by addition of 200 μL saturated ammonium chloride and concentrated to a residue. The compound was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 2-(4-bromo-pyridin-2-yl)-2-cyano-N,N-dimethyl-acetamide and 2-(3-bromo-pyridin-4-yl)-2-cyano-N,N-dimethyl-acetamide.
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[F:14][C:15]([F:44])([F:43])[O:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]1[NH:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:22]=1.[CH3:45]N(C)C=O>>[F:14][C:15]([F:44])([F:43])[O:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]1[NH:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]3[CH2:37][CH2:36][C:35](=[CH:7][C:8]([O:10][CH2:11][CH3:45])=[O:9])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:22]=1
Reactant: CN(C)C=O
Reactant: O=C1CCC(c2ccc(-c3cc(OCc4ccccc4OC(F)(F)F)[nH]n3)cn2)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCC(c2ccc(-c3cc(OCc4ccccc4OC(F)(F)F)[nH]n3)cn2)CC1
Temperature: 25 °C

Procedure:
Methyl 2-(dimethoxyphosphoryl)acetate (0.76 ml, 3.77 mmol) was added dropwise to a stirred and cooled (0° C.) suspension of sodium hydride (0.15 g, 3.76 mmol) in dry N,N-dimethylformamide (10 mL). After 30 minutes of stirring at room temperature, a N,N-dimethylformamide solution of Example 93F (0.748 g, 1.71 mmol) was added to 0° C. After the addition, the solution was allowed to warm to room temperature and stir overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (magnesium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography using 0 to 80% ethyl acetate in hexanes to provide the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:21][Si:22]([Cl:25])([Cl:24])[Cl:23].[Cl:26][SiH:27]([Cl:29])[Cl:28]>>[Cl:23][Si:22]([Cl:25])([Cl:24])[CH2:21][Si:27]([Cl:29])([Cl:28])[Cl:26].[Cl:23][Si:22]([Cl:25])([Cl:24])[CH2:21][SiH:27]([Cl:28])[Cl:26]
Reactant: ClC[Si](Cl)(Cl)Cl
Reactant: Cl[SiH](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 16 %
Yield: 50 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.75 mmol) of triphenylphosphine, 0.92 g (7.5 mmol) of (chloromethyl)trichlorosilane, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 42 hrs. The resulting mixture was distilled to give 1.1 g of 1,1,1,3,3,3-hexachloro-1,3-disilapropane (bp; 173-174° C., yield; 50%) and 0.3 g of 1,1,1,3,3-pentachloro-1,3-disilapropane (bp; 166-167° C., yield; 16%).
Reaction SMILES: [C:1]1(C2CC(=O)NC3C=CC=CC=3S2)C=CC=C[CH:2]=1.[ClH:19].[CH3:20][N:21]([CH3:45])[CH2:22][CH2:23][N:24]([CH3:44])[C:25]([N:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2S[CH:30]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29][CH2:28]1)=[O:26]>>[ClH:19].[CH3:20][N:21]([CH3:45])[CH2:22][CH2:23][N:24]([CH3:44])[C:25]([N:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:2][CH2:1][CH:30]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Reactant: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Sc2ccccc21
Agent: Cl
Product: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)CCc2ccccc21

Procedure:
By substituting an equivalent amount of 3,4,5,6-tetrahydro-4-phenyl-1-benzazocin-2(H)-one, m.p. 188°-189° (prepared as described in Example 1 of U.S. patent application, Ser. No. 418,910, filed Dec. 16, 1964), for the 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-one in part (A) of Example 1 and carrying out the precedure of the Example, there is obtained N-(2-dimethylaminoethyl)-1,2,3,4,5,6-hexahydro-N-methyl-4-phenyl-benzazocine-1carboxamide hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:21]1[N:22]=[N+:23]([O-:32])[C:24]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:21]2[N:22]=[N+:23]([O-:32])[C:24]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: [O-][n+]1nc(Cl)nc2ccc(Cl)cc21
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1nc(Oc2ccc(OCc3ccccc3)cc2)nc2ccc(Cl)cc21
Temperature: 125 °C
Reaction time: 8 h

Procedure:
In a nitrogen atmosphere, a solution of 0.1 mole 4-benzyloxyphenol in 50 cc dimethylformamide is added dropwise at about 15° C. to 0.1 mole 57% sodium hydride in 25 cc dimethylformamide. When evolution of hydrogen ceases, 0.1 mole 3,7-dichloro-1,2,4-benzotriazine-1-oxide is added and the reaction mixture is heated at 125° C. for about 2 hours. After standing overnight at room temperature, the reaction mixture is poured into ice-water (~500 cc). The solid product is filtered and crystallized from methanol or acetonitrile.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.C[C:14](P(OC)(O)=O)([C:16]([O-:18])=[O:17])C.[H-].[Na+].[CH2:26]1COCC1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:14]/[C:16]([O:18][CH3:26])=[O:17]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-quinolinecarboxaldehyde (10 g, 64 mmol) in 200 mL THF was added trimethylphosphonoacetate (11.0 mL, 76 mmol) and then sodium hydride (3.05 g of a 60% suspension in oil, 76 mmol). After stirring for 3 h at room temperature, the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was suspended in ˜75 mL Et2O and to that was added ˜125 mL hexanes and the mixture was placed in the freezer. The solids were collected by filtration to provide 8.46 g (62%) of G5 as a pale orange solid. MS (Electrospray): m/z 214.3 (MH+).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH2:15][C:16]1[N:20]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=2[Cl:29])[N:19]=[C:18]([CH3:30])[CH:17]=1>ClC(Cl)C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:15][C:16]1[N:20]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=2[Cl:29])[N:19]=[C:18]([CH3:30])[C:17]=1[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[Cl:1])=[O:9]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClC(Cl)C(Cl)Cl
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(NC(=O)c2ccccc2Cl)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
A suspension of 2.34 g (17.50 mmol) of aluminum trichloride in 20 mL of 1,1,2,2-tetrachloroethane was treated with 2.02 mL (2.78 g, 15.9 mmol) of 2-chlorobenzoyl chloride and the resulting solution was stirred for 20 minutes at room temperature. Then 2.00 g (7.23 mmol) of the product of Step A was added and the reaction mixture was refluxed for 16 hours. The cooled reaction mixture was poured over ice and the insolubles were filtered off and washed with ethyl acetate. The organic layer was separated and the aqueous was washed twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residues were chromatographed on silica gel, eluting with 4:1 hexane ethyl acetate to give 2.05 g (51%) of the title product, an amorphous foam. Anal. Calcd. for C24H14O2N3Cl5 : C, 52.06: H, 2.55; N, 7.59. Found: C, 52.11; H, 2.57; N, 7.27.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH2:11]([C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22](OCC)=[O:23])=[C:17]2[CH:16]=[CH:15][CH:14]=1)[CH3:12]>C1C=CC=CC=1>[CH2:11]([C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:23])=[C:17]2[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCOC(=O)c1cnn2c(CC)cccc12
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: c1ccccc1
Product: CCc1cccc2c(C(=O)OC3CN4CCC3CC4)cnn12
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
After suspension of 140 mg (1.10 mmol) of 3-quinuclidinol in 20 ml of benzene was refluxed for 0.5 hour by using a Dean-Stark apparatus, 0.05 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 1.5 hours. Unreacted sodium was removed and 80 mg (0.37 mmol) of ethyl 7-ethylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 12 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 100 mg (0.33 mmol) of the title compound were obtained as an oily substance (yield: 91%).
Reaction SMILES: C(CC[N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:15][CH2:14][C:13]([CH2:19][CH2:20][CH3:21])([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[C:6]1=[O:22])#N.CNCCCN.O>C1(C)C=CC=CC=1>[CH2:19]([C:13]1([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:7]2([C:6](=[O:22])[NH:5][C:9](=[O:10])[CH2:8]2)[CH2:11][CH2:12]1)[CH2:20][CH3:21]
Reactant: CCCC1(CCC)CCC2(CC1)CC(=O)N(CCC#N)C2=O
Agent: CNCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1(CCC)CCC2(CC1)CC(=O)NC2=O
Temperature: 25 °C

Procedure:
To a solution of toluene and 4,4 dipropylcyclohexane 1 carboxy 1 acetic acid anhydride (1 equivalent) was added 3 methylaminopropylamine (1.05 equivalents). The reaction mixture was heated at reflux using a Dean Stark trap. Following collection of water (1 equivalent), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[C:11]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:19])[NH:8]1>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]1[C:11]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:19])[NH:8]1
Reactant: CC1(c2ccccc2)OC(=O)NC1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC1(c2ccccc2)OC(=O)NC1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 ml (10 mMole) of thionyl chloride are slowly added dropwise at 0° to +5° C. to 1.04 g (5 mMole) of 4-hydroxymethyl-5-methyl-5-phenyl oxazolidin-2-one dissolved in 15 ml of pyridine. After 1 hour at 50° C., the reaction solution is stirred overnight at room temperature, poured onto ice and repeatedly extracted with chloroform. The combined chloroform phases dried over Na2SO4 are concentrated. The crystals formed are recrystallised from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21](O)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: OCCc1cccc(Cl)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3cccc(Cl)n3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
To a solution of 2-6-chloro-2-pyridinyl)ethanol (Example 470, 250 mg, 1.59 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 698 mg, 3.17 mmol) in THF (4 mL) were added PPh3 (832 mg, 3.17 mmol) and DIAD (641 mg, 3.17 mmol). The reaction mixture was vigorously stirred at rt for 24 h, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (6:1 hexanes/EtOAc) to give the product (170 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 1.72-1.77 (m, 1H), 2.34-2.43 (m, 2H), 2.71 (dd, 1H), 2.81-2.89 (m, 2H), 3.21 (t, 2H), 3.51-3.52 (m, 1H), 4.17 (q, 2H), 4.31 (t, 2H), 6.69 (d, 1H), 6.76 (s, 1H), 7.04 (d, 1H), 7.19 (dd, 2H), 7.57 (t, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].IC>C1COCC1>[CH3:1][C:9]1[C:8]([F:14])=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: [Li]CCCC
Reactant: Fc1ccc(Br)c(F)c1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisoproplylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrous THF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5 M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of TBF is added at a rate to keep the temperature below −65° C. The reaction is stirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of TBF is added to the reaction. The ice bath is removed and the reaction is allowed to warm to room temperature. After 2 hours the reaction is quenched with water and 1N HCl. The aqueous layer is extracted twice with ether. The combined organics are washed with brine and dried over Na2SO4. Removal of the solvent affords the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH3:15]
Reactant: Brc1ccccc1Br
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with acetophenone (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=75 cm) was 3.46 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 1-(2-bromophenyl)-1-phenylethanol (GC retention time: 23.5 min) was obtained in 81% yield. 1H NMR (400 MHz, CDCl3) δ: 1.95 (s, 3H), 3.49 (s, 1H), 7.16 (dt, J=7.6, 1.6 Hz, 1H), 7.20-7.30 (m, 5H), 7.38 (dt, J=7.6, 1.2 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.80 (dd, J=7.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 30.4, 77.4, 122.2, 125.4, 126.7, 127.2, 128.0, 128.3, 129.0, 134.7, 144.7, 147.4. HRMS (EI) m/z: calcd. for C14H13BrO 276.0150, found 276.0155.