Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 90.8 g (0.55 mol) of n-hexyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 125-128° C./0.5 Torr), yielding 100 g of 4-n-hexyloxyphenyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[NH:57]1[CH2:61][CH2:60][CH2:59][C:58]1=[O:62]>>[CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41][N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CCCN1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN2CCCC2=O)cc1

Procedure:
Analogously to Example 27a, 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.19 ml of pyrrolidin-2-one are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (2:1 EtOAc-heptane); Rt=5.88.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][C:46]1[CH:49]=[CH:50][C:43]([O:42][CH3:41])=[CH:44][CH:45]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)[C@H](Cc2ccc(OCC(=O)O)c(C(=O)O)c2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 4-methoxybenzylamine (40 mg) according to Method B to give the title compound (33 mg). 1H-NMR (400 MHz, CD3OD) d 7.75 (s, 1H), 7.34 (dd, 1H), 7.26-7.18 (m, 5H), 7.05 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 2H), 6.82 (m, 2H), 4.77 (s, 2H), 4.56 (m, 1H), 4.15 (dd, J=5.1 Hz, J=14.7 Hz, 1H), 3.76 (s, 3H), 3.08-2.94 (m, 3H), 2.76 (dd, J=9.6 Hz, J=13.7 Hz, 1H), 1.33 (s, 9H); HRMS m/z 649.2615 (calc. of monoisotopic mass for C34H39N3O10 gives 649.2635).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])=[CH:8][C:7]([Cl:21])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=1>CN(C=O)C>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]2=[N:16][N:17]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=3)[N:18]=[C:19]2[C:11]=1[O:10][C:9]1[CH:8]=[C:7]([Cl:21])[CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1Cl
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2nc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4Cl)c3n2)c2cccnc21
Reaction time: 1 h

Procedure:
2,5-dichloro-3-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (1.00 g, 2.94 mmol) and cesium carbonate (1.15 g, 3.53 mmol) were suspended in dry DMF (10 mL) under N2, and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.965 g, 3.09 mmol) was added as a solution in DMF (5 mL) at room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (50 mL), and the mixture extracted with EtOAc (2×100 mL). The combined organic fractions were washed with water (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (120 g) eluting with 25-50% EtOAc/hexanes. LRMS (M+1)=569.6.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH:5]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2nccs2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1csc(-c2cc[nH]c2)n1

Procedure:
To a stirred solution of 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole (200 mg, 0.65 mmol) in 2 mL THF was added dropwise tetrabutylammonium fluoride (0.98 mL of 1M in THF, 0.98 mmol), after 20 minute the reaction was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 2-(1H-pyrrol-3-yl)-1,3-thiazole as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:13])[C:3]=1[CH2:10][CH3:11]
Reactant: CCc1c(Br)cccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1c(Br)cccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of (3-bromo-2-ethylphenyl)methanol (D133) (3 g, 13.95 mmol) in Dichloromethane (DCM) (50 mL) was added CBr4 (5.55 g, 16.74 mmol). To the reaction solution was added triphenylphosphine (5.49 g, 20.92 mmol) portionwise at 0° C. The reaction solution was warmed to room temperature and stirred at the temp overnight. The solvent was removed in vacuo and the residue was purified by ISCO column chromatography to afford 1-bromo-3-(bromomethyl)-2-ethylbenzene (D134) (1.3 g) as an oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1>C(O)(C)C>[CH3:3][S:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: CSc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1ccc(CO)cc1
Yield: 98.7 %

Procedure:
Sodium borohydride (3.78 g) was added to isopropyl alcohol (50 ml) and the mixture was stirred under ice-cooling. Thereto was dropwise added 4-(methylthio)benzaldehyde (15 g) and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled away and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was recrystallized from hexane-ethyl acetate to give the subject compound (15 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH2:32][CH:30]1[CH2:31][N:28]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:29]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2[nH]cc(CC3CNC3)c2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2c[nH]c4ccc(F)cc24)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.35 g,.0.80 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1H-indole (0.19 g, 0.96 mmol) and triethylamine (0.16 mL, 1.2 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.090 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate and collected as 0.068 g of a yellow solid, m.p. 125° C. (dec).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)C(C)N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BA above and using phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)C(=O)OC(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N(CCCCl)CCc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCNCCCCl)cc1

Procedure:
A solution of 626 mg (1.94 mmol) of tert.-butyl (3-chloropropyl)-[2-(4-cyanophenyl)ethyl]carbamate and 5.0 ml of trifluoroacetic acid in 20 ml of dichloromethane was stirred at room temperature for 1.5 hours and then evaporated to dryness. The residue was triturated with diethyl ether. The precipitate formed was then filtered off and dried under reduced pressure over calcium chloride. The product obtained in this manner was reacted further without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>O.C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
The starting material is prepared as follows: To the stirring mixture of 244 g of p-hydroxybenzaldehyde, 360 g of potassium carbonate, 32 g of potassium iodide, 1.2 lt of 95% aqueous ethanol and 160 ml of water is added slowly 367 g of m-chlorobenzyl chloride. The mixture is stirred at reflux for four hours, cooled to 80° and 2 lt of warm water are added while stirring. The mixture is cooled, the precipitate collected, washed with water and recrystallized from methanol, to afford the 4-(3-chlorobenzyloxy)-benzaldehyde melting at 51°-54°.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.[F:19][C:20]([F:28])([F:27])[C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C.S(=O)(=O)(O)O>[F:19][C:20]([F:28])([F:27])[C:21]([C:22]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:24])=[O:26]
Reactant: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCC2
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-fluoro-phenyl)-methanone in 2 ml acetic acid was added 0.024 ml (0.19 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 10 mg (14%) 2,2,2-trifluoro-1-[4-(4-fluoro-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light brown solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].OS(O)(=O)=O.[CH3:17]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: CO
Reactant: O=C(O)CCCCCCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCBr

Procedure:
Under N2 atmosphere, 8-bromooctanoic acid was dissolved in dry methanol. Concentrated H2SO4 was added drop-wise and the reaction mixture was stirred under reflux for three hours.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1>CCOCC>[Br:2][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCCCc1c[nH]c2ccccc12
Solvent: CCOCC
Product: BrCCCc1c[nH]c2ccccc12
Temperature: 23 °C
Yield: 14.8 %

Procedure:
Phosphorus tribromide (17.4 g) in Et2O)30 mL) was added dropwise to a Et2O solution (100 mL) containing 3-(3-hydroxypropyl)indole (VI; 7.5 g) at 0° C. with stirring and under N2 atmosphere. After the addition was complete, the reaction was allowed to warm to 23° C. and continuously stirred for 16 h. At the end of this time, the reaction was cooled to 0° C. and ice (ca. 25 mL) added portionwise and stirred an additional 2 h. The organic phase was separated from the aqueous phase and the aqueous layer extracted with Et2O. The combined organic phases were washed with sat. NaCl solution, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3-(3-bromopropyl)indole (V; 1.51 g; 15%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:28]3[CH2:29][CH:30]=[C:31]([C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][CH:35]=4)[CH2:32][CH2:33]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.52 g (1.3 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.80 g (4.1 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 20 mL of DMSO was heated at 65° C. for 3 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.11 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 175-177° C.
Reaction SMILES: Cl.Cl.C(OC1C=CC([CH:17]([N:26]2[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]2)[CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=CC=1[Cl:34])C1C=CC=CC=1.Cl.Cl.N[C@@H]1CCN(CC(C2(O)CCCCC2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:47]([Cl:59])[CH:46]=2)C1>>[ClH:34].[ClH:59].[CH2:52]([O:51][C:48]1[CH:49]=[CH:50][C:45]([CH:18]([C:19]2([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:17][N:26]2[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]2)=[CH:46][C:47]=1[Cl:59])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: N[C@@H]1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)C1
Reactant: CN(C)[C@@H]1CCN(C(CC2(O)CCCCC2)c2ccc(OCc3ccccc3)c(Cl)c2)C1
Agent: Cl
Product: CN(C)[C@@H]1CCN(CC(c2ccc(OCc3ccccc3)c(Cl)c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 36, 1-{-[4-(benzyloxy)-3-chlorophenyl]-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol (See Example 383). MS (ES) m/z 457.1; HRMS: calcd for C27H37ClN2O2+H+, 457.26163. found (ESI, [M+H]+), 457.2608.
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]([CH2:2][C:3]([CH3:5])=[CH2:4])[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
At 25° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added dropwise to a solution of N-(2-bromo-5-nitrophenyl)acetamide (3.6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 mL). The reaction mixture was stirred at 25° C. overnight. The reaction mixture was then filtered and the filtrate was treated with sat. Na2CO3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to provide N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide as a golden solid (3.1 g, 85%). ESI-MS 313 m/z (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:36][C:26]34[CH2:27][CH:28]5[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]5)[CH2:35]3)[CH2:33]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(NC34CC5CC(CC(C5)C3)C4)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.078 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:39])([CH3:40])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (85 mg, 0.25 mmol) (Example B.7) according to general procedure II. Obtained as a yellow solid (61 mg, 42%). MS (ISP) 585.3 [(M+H)+]; mp 192-195° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)=[O:18]
Reactant: CNOC
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A suspension of 1-(4-nitrophenyl)piperidine-4-carboxylic acid (0.76 g, 3.0 mmol) in dichloromethane (15 mL) is cooled to 0° C. in an ice-water bath. Carbonyldiimidazole (0.59 g, 3.6 mmol) is added and the mixture is allowed to warm to room temperature. An additional volume of dichloromethane (10 mL) is added and the mixture continued to stir for 30 minutes before the addition of N,O-dimethylhydroxylamine hydrochloride (0.73 g, 7.5 mmol). After stirring overnight, the reaction mixture is filtered. The insoluble material is washed with diethyl ether, and the combined filtrate is washed with 5% aqueous potassium hydrogen carbonate solution, water, and saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide as a bright yellow powder (0.84 g, 95%).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[N+:19]([O-])=O)#[N:2].ClCCl.N>CO>[C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[NH2:19])#[N:2]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(OC2CCCC2)c1OC
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)c(C#N)c(OC2CCCC2)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-3-cyclopentyloxy-4,5-dimethoxynitrobenzene following the procedure described in Example 10(f) and was obtained as a cream coloured solid (66%). Rf 0.79 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). 1H-NMR (CDCl3): Γ=1.57 (2H, m), 1.70 (2H, m), 1.90 (4H, m), 3.68 (3H, s), 3.82 (3H, s), 5.10 (1H, m), 5.98 (1H, s).