Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16](=[O:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:6]=[C:7]([O:14][CH3:15])[C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:14][CH3:15])[C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH:16]([OH:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1-n1cccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1-n1cccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.54 g. of 3',5'-dimethoxy-2-(methylsulfonyl)-4'-(pyrrol-1-yl)-acetophenone in 20 ml. of ethanol and 20 ml. of water was treated with a solution of 0.4 g. of sodium borohydride in 5 ml. of water with addition of 0.1 g. of sodium hydroxide. The mixture was stirred at room temperature for an additional 3 hours, cooled with ice, diluted with 50 ml. of water and filtered under vacuum. After recrystallization from ethanol, there was obtained 3,5-dimethoxy-α-[(methylsulfonyl)-methyl]-4-(pyrrol-1-yl)-benzyl alcohol having a melting point of 192° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([O:14][C:15](=[O:23])[CH:16](Cl)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15](=[O:23])[CH:16]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc2ccccc2c1)C(=O)OCC
Yield: 92.6 %

Procedure:
This compound was prepared following Procedure 33. Thus, a mixture of 43.2 g (0.3 mole) of 2-naphthol, 70 g (0.36 mole) of diethylchloromalonate and 69.1 g (0.5 mole) of anhydous potassium carbonate in 750 ml of acetone gave 84.0 g (93%) of a tan solid. An analytical sample, mp 57°-58.5° C. (lit.1 mp 57°-58° C.), was recrystallized from isopropyl ether.
Reaction SMILES: [BrH:1].[O:2]1[CH2:13][CH:3]1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>>[Br:1][CH2:13][CH:3]([OH:2])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: CCOP(=O)(CC1CO1)OCC
Reactant: Br
Product: CCOP(=O)(CC(O)CBr)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
(1)-(a) 47% Aqueous hydrobromic acid (82.8 g) was added dropwise to diethyl 2,3-epoxypropylphosphonate (77.6 g) under ice-cooling and with stirring over a five minutes interval. After the stirring was continued for an hour under ice-cooling and for 3 hours at ambient temperature, the reaction mixture was extracted with ethyl acetate (500 ml). The ethyl acetate layer was separated, washed three times with saturated aqueous sodium bicarbonate solution (200 ml and 100 ml×2) and twice with saturated aqueous sodium chloride solution (100 ml×2), dried over magnesium sulfate and evaporated to dryness to give oily diethyl 3-bromo-2-hydroxypropylphosphonate (94.7 g)
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH:28]1[CH2:32][CH2:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH3:42])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:41]([CH2:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:29]4[NH:30][CH2:31][CH2:32][N:28]=4)=[CH:38][CH:37]=3)[CH3:42])=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (100 mg, 0.26 mmol), the bis HCl salt of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (65 mg, 0.23 mmol), EDCI (60 mg, 0.31 mmol), HOBt (42 mg, 0.31 mmol) and DIPEA (0.2 mL, 1.04 mmol) in DMF (8 mL).
Reaction SMILES: [Na].Br[C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.[CH2:9]([OH:11])[CH3:10]>>[CH2:9]([O:11][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)[CH3:10]
Reactant: CCO
Reactant: Brc1cncnc1
Agent: [Na]
Product: CCOc1cncnc1
Reaction time: 60 h
Yield: 25.6 %

Procedure:
Sodium (2.89 g. 125.8 mmol) was dissolved in ethanol (110 mL) and 5-bromopyrimidine (10.0 g, 62.9 mmol) added. The reaction was heated at 120° in an autoclave for 17 h and then allowed to stand at 23° for 60 h. The ethanol was removed under reduced pressure and water (5 mL) added to the concentrate. The aqueous phase was extracted with CH2Cl2 (4×100 mL). The combined organic extracts were washed with saturated NaCI solution, dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure. Silica gel chromatography (Hexane/EtOAc; 70:30) of the concentrate yielded 5-ethoxypyrimidine (2.00 g, 25.6%).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[C:36]1(=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>CCCCCC.C1CCCCC1>[N:10]12[CH2:16][CH2:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][CH:9]2[CH2:8][C:7]([C:36]1([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCCC1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: OC1(C(CC2CC3CCN2CC3)(c2ccccc2)c2ccccc2)CCCC1
Reaction time: 1.2 h

Procedure:
A solution of 20.4 parts 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane, 10.5 parts by volume of N,N,N',N'-tetramethylethylenediamine, 48 parts by volume of a 1.6 M solution of butyllithium in hexane in 500 parts by volume of cyclohexane is heated to reflux while being stirred for 1.2 hours under nitrogen. The reaction mixture is cooled to 10 and 6.8 parts by volume of cyclopentanone is added during 5 minutes. It is washed four times with water and one time with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual solid is triturated with 40 parts diethyl ether and filtered. The filtrate is evaporated under reduced pressure to give residual solid and oil. This residue is put on a 25 mm volume of Woelm silica gel and eluted with a mixed solvent of ethanol, concentrated ammonia and toluene (ratio 2:0.25:98) under a pressure to maintain a flow rate of 8 ml per minute. The desired fraction is evaporated under reduced pressure giving residual oil which solidifies. The solid is washed with n-pentane and recrystallized from diethylether giving the product as a white solid: (XI) 1-[2-(1-azabicyclo [2.2.2]octan-2-yl)-1,1-diphenylethyl]cyclopentanol m.p. 178°-179.5°, MW 376. The hydrochloride of this compound is crystallized from a mixed solvent of isopropanol and diethyl ether: 1-[2-(1-azabicyclo[2.2.2]octan-2-yl)-1,1-diphenylethyl] cyclopentanol hydrochloride (XVII); m.p. 247°-249°; MW 412.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])#[CH:18]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: C#Cc1ccccc1F
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3ccccc3F)c2c2ccccc12
Yield: 74.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynyl-2-fluorobenzene (0.07 mL, 0.65 mmol) to provide 259 (101 mg, 75% yield) as a tan solid. LC-MS (M+H=315 obsd.=315).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[C:11]1([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccnc1Nc1ccccc1
Yield: 80 %

Procedure:
3-nitro-N-phenylpyridin-2-amine (29 g, 135 mmol) and palladium on carbon (10 wt %, 3 g) in ethanol (200 mL) were hydrogenated on a Parr hydrogenator at 45 psi for 8 h. The catalyst was filtered. The solution was concentrated to give N2-phenylpyridine-2,3-diamine (20 g, 80% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][NH:44][C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[OH:51][CH:49]1[CH2:48][N:47]([CH2:46][C@@H:45]([N:44]([CH3:43])[C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2)[CH2:52][CH2:53][CH3:54])[CH2:50]1
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CCC[C@@H](CN1CC(O)C1)NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.2 %

Procedure:
3,4-Dimethylbenzoic acid (0.174 g, 1.16 mmol), TBTU (0.373 g, 1.16 mmol) and DIPEA (0.303 mL, 1.74 mmol) was stirred in DCM (2 mL) for 40 min before (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.1 g, 0.58 mmol) was added. The resultant mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 1 mL, 1M). The resultant mixture was stirred at rt for 90 min before the MeOH was removed on a vacuum centrifuge. The crude product was extracted with DCM and concentrated under reduced pressure. To the residue was DMSO (1 mL), DCM (3 mL) and KOH (1M solution, 3 mL) added. The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated, water (5 mL) and DCM (5 mL) was added and the pH was adjusted to 12 using KOH (1M solution). The organic layer was filtered through a phase separator and the solvent was removed under reduced pressure to give the title compound (48 mg, 27%). Mixture of rotamers: (600 MHz, DMSO-d6) δ 0.69-0.78, 0.85-0.93, 0.94-1.06, 1.08-1.50, 2.19-2.28, 2.32-2.41, 2.44-2.56, 2.56-2.65, 2.66-2.76, 3.27-3.38, 3.43-3.55, 4.03-4.20, 4.44-4.52, 5.17-5.26, 6.97-7.21. Total no of protons: 28. HRMS (M+H)+: calculated 305.2229. found 305.2214.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1.C(O)(C(F)(F)F)=O.[I:24]N1C(=O)CCC1=O.[NH4+].[OH-]>C(O)(=O)C>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:24])[C:8](=[O:11])[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1ccc(Cc2ccc(F)cc2F)c[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=c1[nH]cc(Cc2ccc(F)cc2F)cc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2,4-difluorobenzyl)pyridin-2(1H)-one 3 (1.89 g, 8.5 mmol) in acetic acid (34 ml) was added TFA (2.2 ml), followed by N-iodosuccinimide (2.02 g, 8.5 mmol). The red homogeneous solution was allowed to stir overnight at room temperature, poured onto ice and neutralized with cone. NH4OH. The solid was collected by filtration, rinsed with water, treated with methanol/dichloromethane, dried over sodium sulfate, and evaporated. The resulting brown solid was purified by flash column chromatography on silica gel (hexanes:ethyl acetate, 50:50). Yield 2.57 g (87%). 1H NMR (CDCl3, 500 MHz): δ 13.20 (s, 1H), 7.98 (d, 1H, J=2.2 Hz), 7.26-6.81 (m, 4H), 3.70 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 162.5, 161.9, 160.5, 151.9, 133.5, 131.2, 121.8, 120.0, 111.6, 104.3, 91.6, 29.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:10]=1>C(OCC)(=O)C.[Pt]=O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:10]=1
Reactant: COC(=O)CCCC=Cc1nn(-c2ccc(F)cc2)c2c1CCC2
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCc1nn(-c2ccc(F)cc2)c2c1CCC2
Reaction time: 3 h

Procedure:
A solution of the compound of Example 29 (0.90 g, 2.7 mmol) in ethyl acetate (100 ml) was treated with platinum oxide (0.4 g) and reduced for 3 hours at atmospheric pressure. The catalyst was filtered, the filtrate evaporated and the residue (0.87 g) was crystallized from hexane to yield the title compound, m.p. 39°-40° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19](=[O:21])[CH3:20])=[C:7]([CH3:22])[NH:6][C:5]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)(=[O:3])[CH3:2].[I-].[Na+].[ClH:32].[C:33]1([C:39]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C.C(OCC)C>[ClH:32].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19](=[O:21])[CH3:20])=[C:7]([CH3:22])[NH:6][C:5]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:42]1[CH2:43][CH2:44][C:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:40][CH2:41]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(CCCCCCBr)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)C1=C(C)NC(CCCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
3.5 g (7.8 mmol) 3,5-diacetyl-1,4-dihydro-2-(6-bromohexyl)6-methyl-4-(3-nitrophenyl) -pyridine are reacted first with 2.3 g (15.6 mmol) sodium iodide, as described for starting compound B, and then with 4.3 g (15.6 mmol)4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=8/2. The product thus obtained is taken up in 5 ml acetonitrile and the mixture is diluted with 5 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 3 g (61%). M.p. 166°-167° C. (acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[CH3:24][N:25]([CH3:29])[CH2:26]CO>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=1[C:15]([O:17][CH2:18][CH2:24][N:25]([CH3:29])[CH3:26])=[O:16]
Reactant: CN(C)CCO
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2c(Cl)cccc12
Product: CN(C)CCOC(=O)c1cc(F)ccc1Nc1ccnc2c(Cl)cccc12

Procedure:
Using the procedure of Step B of Example 7, 6.61 g of the product of Step A and 4 ml of anhydrous 2-dimethylamino-ethanol were reacted to obtain 6.8 g of 2-dimethylamino-ethyl 2-(8-chloro-4-quinolinylamino)-5-fluoro-benzoate melting at 121°-122° C. 5.245 g of the said product were dissolved in 10 ml of anhydrous ethanol and 2.05 ml of an ethanol solution of 6.6 N hydrochloric acid were added thereto. The mixture was ice cooled and was vacuum filtered and the recovered product was washed with a 1-4 ethanol-ether mixture to obtain 5.34 g of the desired hydrochloride melting at 198° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1cccc(Cl)c1Cl
Product: Nc1ncc2cc(-c3cccc(Cl)c3Cl)c(N)nc2n1

Procedure:
Following the procedure of Example 1, 2,3-dichlorophenylacetonitrile was reacted with 2,4-diamino-5-pyrimidinecarboxaldehyde to give the title compound; mp 366°-369° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[C:5]([NH2:15])[NH:4][N:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[CH:19]=[C:20]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:32])([F:33])[F:16])[CH:19]=4)=[CH:25][C:26](=[O:27])[NH:15][C:5]=23)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(C(F)(F)F)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
3-Methyl-4-(4-methoxyphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate (307 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 270 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:13]([NH2:16])[CH2:14][CH3:15]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](=[O:11])(=[O:10])[NH:16][CH2:13][CH2:14][CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCN
Solvent: CCCCO
Product: CCCNS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorobenzenesulphonyl chloride (500 mg 2.1 mmol) and 1-propylamine (0.2 ml, 2.4 mmol) in n-butanol (10 ml) was heated at reflux for 48 hours. The volatiles were removed by evaporation and the residue triturated with diethylene ether and the product collected by filtration to give the title compound. NMR: 0.78 (t, 3H), 1.35 (q, 2H), 2.79 (t, 2H), 7.60 (dd, 1H), 7.84 (d, 1H), 7.92 (d, 2H)
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(N)c(Br)c1
Product: Cc1ccc(N)c(-c2ccc(Cl)cc2)c1

Procedure:
2-bromo-4-methylaniline and 4-chlorobenzene boronic acid were combined to form 2-(4-chlorophenyl)-4-methylaniline,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH2:30][CH:31]2[NH:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:36]2[CH:31]([CH2:30][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:32][CH2:33][CH:34]([OH:37])[CH2:35]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCC(CN2CCCC2)NC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CC(O)CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
A solution of 3,4-dichlorophenylacetic acid (0.64 g) in dry dichloromethane (15 ml) was treated with 1,1'-carbonyldiimidazole (0.51 g) portionwise over a 5 minute period. The mixture was stirred at ambient temperature for 40 min and was added to a solution of the product of stage (ii) (0.55 g) in dichloromethane (20 ml). The reaction mixture was stirred at ambient temperature for 18 h, diluted with dichloromethane (50 ml) and washed with aqueous sodium carbonate solution (2M; 2×10 ml). The organic extract was dried, filtered, and evaporated in vacuo to give an oily residue (1.1 g). The residue was purified by flash chromatography using dichloromethane methanol/ammonia (200:8:1) as eluent to give the title compound as an oil (0.32 g). T.l.c. Silica(dichloromethane/methanol/ammonia 150:8:1) Rf 0.5.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:3]2[CH2:1][CH3:2])=[CH:21][CH:20]=1
Reactant: CCC1Nc2ccccc2C12CCN(C)CC2
Reactant: Fc1ccc(Cl)cc1
Product: CCC1N(c2ccc(Cl)cc2)c2ccccc2C12CCN(C)CC2

Procedure:
By following the procedure of Example 1c, 2-ethyl-1'-methylspiro[indoline-3,4'-piperidine], the free base of part a, is treated with 4-chlorofluorobenzene to yield 1-(4-chlorophenyl)-2-ethyl-1'-methylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16](=O)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C:19](O[K])(C)(C)C>C1COCC1>[C:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:16]=1[CH3:17])[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])([CH3:1])=[CH2:19]
Reactant: CC(C)(C)O[K]
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: C=C(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a nitrogen-filled glove box, to 250 ml round bottomed flask fitted with a magnetic stirring bar containing 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)ethanone (0.5 g, 2.05 mmol) and 50 ml of dry THF was added [+PPh3MeI−] (1.24 g, 3.07 mmol), followed by tBuOK (343 g, 3.06 mmol). The mixture was stirred at room temperature. After 24 h, in situ GC/MS analysis showed complete conversion of the carbonyl compound to the alkene product. The mixture was filtered to remove the salt. The solvent was removed in vacuo and the resulting solid was redissolved in hexane and then cooled in the refrigerator for 24 h to crystallise the PPh3O. The mixture was filtered and cooled again to remove additional PPh3O. This step has to be repeated at least 4 times to remove all of the PPh3O. Finally, the solvent was removed in vacuo to obtain the pure alkene. Alternatively, a faster method of purification, after removal of the salt by filtration, involves concentration in vacuo and then Kugelrohr distillation (100-140° C., 3×10−4 torr), which gave an analytically pure sample of 4a (396 mg, 80%); m.p. 39-40° C.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Br.[N+:16]([C:19]1[C:24]2[NH:25]CCNC(=O)C=2C=CC=1)([O-])=O>>[F:10][C:8]1[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]2[NH:16][CH2:19][CH2:24][NH:25][C:3](=[O:15])[C:4]=2[CH:9]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1Br
Reactant: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Product: O=C1NCCNc2c1cc(F)cc2[N+](=O)[O-]

Procedure:
This compound was prepared from 2-bromo-5-fluoro-3-nitro-benzoic acid methyl ester according to the procedure described in Example 2 for the intermediate f. Obtained 2.20 g (68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CCC(C#N)c1ccc(F)cc1
Product: CCC(C1=NCCN1)c1ccc(F)cc1

Procedure:
rac-2-[1-(4-Fluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(4-fluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 207.0 ((M+H)+.).