Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:11]=1[C:12]([NH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])=[O:13].C(N(CC)CC)C>O1CCOCC1>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]1[N:14]=[C:12]([C:11]2[C:10]([F:9])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[O:13][C:2]1=[O:3]
Reactant: O=C(NNc1ccccc1Br)c1c(F)cccc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2F)nn1-c1ccccc1Br

Procedure:
2.3 ml (19 mmol) of trichloromethyl chloroformate are added dropwise at 10°-20° C. to a mixture of 5.34 g (16 mmol) of 2,6-difluoro-N'-(o-bromophenyl)-benzhydrazide and 5.50 ml (40 mmol) of triethylamine in 35 ml of dioxan. The reaction mixture is heated at the reflux temperature for a further 3 hours and the solvent and excess reagent are subsequently distilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is washed in each case once with water and sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After crystallization of the residue from acetone/n-hexane there is obtained pure 3-(2-bromophenyl)-5-(2,6-difluorophenyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 111°-114° C.; IR spectrum: 1790 cm-1 ; mass spectrum: 354/352(15), 310/308(7), 171/169(41), 90(100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[OH:13][CH2:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: NCCCO
Reactant: [O-][n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: [O-][n+]1ccccc1NCCCO
Temperature: 67 °C
Reaction time: 23 h
Yield: 80.3 %

Procedure:
A mixture of 2-chloropyridine-N-oxide (16.6 g, 100 mmoles), 3-amino-1-propanol (15.3 ml, 200 mmoles), NaHCO3 (42 g, 0.5 mole), and tert-amyl alcohol (100 ml) was heated to reflux. After 23 hours, the reaction was cooled, diluted with CH2Cl2 (300 ml), and filtered to remove insoluble materials. The filtrate was concentrated to afford a brown oil. The oil was dried under vacuum overnight. Ether (100 ml) was added to give a brown solid. The ether was decanted and the solid was washed further with ether/acetonitrile (3/1). The resulting solid was heated at 67° C. under vacuum to give the desired product (13.5 g). 1H NMR was consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:27])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[ClH:27].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCCSc1ccncc1
Yield: 84.3 %

Procedure:
To a solution of.1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.61 ml (4.96 mmol) of pivaloyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.01 g of the desired compound (free base) (96.4%, yellow oil).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([CH3:24])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[Cl:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32][C:4]([C:6]2[N:7]=[C:8]([CH3:24])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([F:21])([F:23])[F:22])[CH:13]=3)[C:10]=2[CH3:11])=[O:5])[CH:29]=[CH:28][N:27]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CCOC(=O)c1nc(C)n(-c2ccc(OC)c(C(F)(F)F)c2)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c(C)nc(C(=O)Cc3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-(4-Methoxy-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.8 g, 2.3 mmol) and 2-chloro-4-methylpyridine (0.36 g, 2.8 mmol) were dissolved in 10 mL toluene. This solution was dropped to a cold (0° C.) mixture of potassium bis(trimethylsilyl)amide (1.17 g, 5.84 mmol) in 15 mL toluene. The reaction mixture was stirred for 90 min. at 0° C. 0.4 mL acetic acid were added, and the mixture extracted with water, saturated NaHCO3-Solution and brine. The aqueous layer was washed with toluene (100 mL). The combined organic extracts were dried with sodium sulfate and filtered. The solvent was evaporated, and the crude product [(0.8 g, 81%), [MS: m/e=424.5 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1ccccc1Br
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2Br)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-bromo-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.06 (br, 1H), 7.76 (br, 1H), 7.69 (2H), 7.41 (t, 1H), 7.16 (t, 1H), 7.05-6.95 (2H), 6.47 (br, 1H), 3.96 (t, 2H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 398, 400.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[CH:18]=[C:17]([CH3:19])[C:14]([C:15]#[N:16])=[C:13]([CH3:20])[N:12]=1.[OH-].[Na+]>O>[OH:10][C:11]1[C:18]([N+:1]([O-:4])=[O:2])=[C:17]([CH3:19])[C:14]([C:15]#[N:16])=[C:13]([CH3:20])[N:12]=1
Reactant: Cc1cc(O)nc(C)c1C#N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(O)c([N+](=O)[O-])c(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a stirring mixture of nitric acid (fuming, 36 mL) and sulfuric acid (18 mL) was added 6-hydroxy-2,4-dimethylnicotinonitrile (step 1, 9.0 g, 60.8 mmol) in one portion, and the mixture was stirred at room temperature. After 1 h, the mixture was poured in water (100 mL) and neutralized with 2N aqueous NaOH. The resulting precipitates were collected by filtration to afford 3.2 g (27%) of the title compound: 1H-NMR (DMSO-d6) δ 2.28 (3H, s), 2.11 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:13](=[O:15])[NH:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)C(NC(=O)OCc1ccccc1)C(O)C(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoic acid (368 mg, 1.31 mmol) in anhydrous tetrahydrofuran (5 ml) was added hydroxybenzotriazole (177 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol). The resulting solution was stirred at room temperature under nitrogen for 30 minutes. A solution of 1-amino-3,3-diethoxypropane (183 mg, 1.25 mmol) in tetrahydrofuran (2 ml) and N,N-diisopropylethylamine (0.228 ml, 169 mg, 1.31 mmol) were added and stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (75 ml) and water (40 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×75 ml). The combined extracts were washed with 2% cold hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to provide [1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 79%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[Cl:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1cc(Cl)ccc1Cl
Temperature: 50 °C
Yield: 50.1 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 444 mg, 2.0 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 274 mg, 1.44 mmol), copper(II) acetate (363 mg, 2.0 mmol) and triethylamine (280 μL, 2.0 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (265 mg, 50%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27])(=[O:23])=[O:22].CC1C=CC([N+]([O-])=O)=CC=1S(N)(=O)=O.FC(F)(F)C(O)=O>Cl.CC(O)C>[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[CH3:31])(=[O:22])=[O:23]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C#CCOc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol, made by reduction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (I) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1)[CH2:5][CH2:6][S:7]([CH3:10])(=O)=O.[CH2:25]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([S:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C@H:32]1[CH2:44][NH2:45])=[O:30])[CH:26]=[CH2:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([S:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][C@H:32]1[CH2:44][NH:45][S:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12](=[O:23])[NH:11][C@H:4]([C:3]([O:2][CH3:1])=[O:24])[CH2:5][CH2:6][S:7][CH3:10])[CH:14]=1)(=[O:21])=[O:20])=[O:30])[CH:26]=[CH2:27]
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNS(=O)(=O)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 15(a) (1.53 g. 4.18 mmol) in CH2Cl2 (20 mL) was added to a stirred solution of (2S,4S)-2-aminomethyl-4-BOCsulfanyl-pyrollidine-1-carboxylic acid allyl ester (15(b)) (prepared as described in International Patent Application WO 92/17480. see pages 39-41) (1.32 g. 4.18 mmol) and (iPr)2NEt (1.5 mL. 9.0 mmol) in CH2Cl2 (30 mL) at 0° C. under argon. The resulting solution was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then washed with water (100 mL), dried over MgSO4, filtered and concentrated to a viscous white gum. This was then purified by flash chromatography on 9385 SiO2. eluting with a gradient of 35-50% EtOAc/i-Hexane to give (2S,4S)-4-BOCsulfanyl-2-{[3-([1S]-1-methoxycarbonyl-3-methylsulfanyl-propylcarbamoyl)-benzenesulfonylamino]-methyl }-pyrrolidine-1-carboxylic acid allyl ester (15(c)) as a colourless foam: 2.19 g (81.3%).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([F:43])[CH:37]=2)([C:33](O)=[O:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:30]2([C:33]([N:16]3[CH2:15][CH2:14][N:13]([C:11]4[C:12]5[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=5[N:8]=[CH:9][N:10]=4)[CH2:18][CH2:17]3)=[O:34])[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:32][CH2:31]2)=[CH:37][C:38]=1[F:43]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(F)c2)CC1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)c(F)c5)CCN(C(=O)OC(C)(C)C)CC4)CC3)c21
Reaction time: 4 h
Yield: 22.9 %

Procedure:
(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (35.0 mg, 0.114 mmol) and 1-(tert -butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid (40.8 mg, 0.114 mmol) were dissolved in DCM (1.1 mL) and treated with DIEA (0.0595 ml, 0.342 mmol) at ambient temperature. The mixture was allowed to homogenize before the HBTU (47.5 mg, 0.125 mmol) was added in one lot. The reaction was allowed to stir for four hours to completion by LCMS analysis of the crude. The reaction was diluted with DCM, washed with diluted NaHCO3 solution, washed with water, washed with brine, and separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 5% methanol in ethyl acetate) to afford the pure tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate (15.0 mg, 22.9% yield) as a pale yellow oil. MS (APCI+) [M+H]+574; Rf: 2.92.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.C(=O)([O-])O.[Na+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 12.9 parts of 4-(1-piperazinyl)-phenol dihydrobromide, 40 parts of ethanol and 50 parts of water are added 12.6 parts of sodium hydrogen carbonate. Then there are added dropwise 6.4 parts of methanesulfonyl chloride at 0° C. Upon completion, stirring is continued overnight. The precipitated product is filtered off and taken up in water. The whole is alkalized with a sodium hydroxide solution and stirred for 30 minutes at room temperature. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 2.8 parts of 1-(4-hydroxyphenyl)-4-(methylsulfonyl)-piperazine; mp. 204.9° C.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1[O:17]C=C[N:20]=1)([O-])=O.Cl>CC(C)=O.O>[S:13]1[C:12]2[C:16](=[O:17])[NH:20][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:10][C:11]=2[CH:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccccc1Cc1ccsc1-c1ncco1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1Nc2ccccc2Cc2ccsc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.1 %

Procedure:
A mixture of 5.0 g of the product of Example 5 in 100 ml of 3:1 acetone-water containing 30 ml of 1N HCl is refluxed for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in 100 ml of glacial acetic acid. The mixture is stirred at 70° C. while 10.0 g of zinc dust is slowly added. Stirring is continued for 6 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is evaporated in vacuo to a residue which is extracted with chloroform. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 2.9 g of the desired product as a brown solid, M+ =215.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:17]([OH:20])(=[O:19])=[O:18].Cl.C[O-].[Na+:24]>C(Cl)(Cl)Cl>[S:17]([O-:20])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])=[O:18].[Na+:24]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methyltridecanol (107 g, 0.5 mol), prepared as an intermediate in Example I. Chlorosulfonic acid (61.3 g, 0.52 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with an ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until a aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added methanol (1L) and 300 ml of 1-butanol. Vacuum filter off the inorganic salt precipitate and remove methanol from the filtrate on a rotary evaporator. Cool to room temperature, add 1L of ethyl ether and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (76 g, 90% active by cat SO3 titration).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: O=C1CCc2cc(Cl)c(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Yield: 69 %

Procedure:
A solution of 12.3 g of 5,6-dichloro-1-indanone, 12.6 ml of 3-buten-2-ol and 125 mg of p-toluenesulfonic acid in 125 ml of 2,2-dimethoxy-propane was boiled under reflux for 68 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.3 g of educt, there were obtained 10.8 g (69%) of (RS)-2-(2-buten-1-yl)-5,6-dichloro-1-indanone as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C1CCN2C(=NCCC2)CC1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(Cc1ccccc1)NC(=O)Nc1ccc(Cl)cc1
Yield: 98.9 %

Procedure:
To a solution of phenylalanine methyl ester hydrochloride (2.0 g) and DBU (1.4 ml) in acetonitrile (40 ml) was added 4-chlorophenyl isocyanate (1.4 g). The reaction mixture was mixed at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as colorless powder (3.0 g, 97%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[I-].[Mg+2].[I-].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:23][CH3:24])=[C:14]([CH:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])[CH:15]=1>ClCCl.CO>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:23][CH3:24])=[C:14]([CH:16]2[C:20](=[O:21])[CH:19]3[CH:18]([CH:5]4[O:1][CH:2]3[CH:3]=[CH:4]4)[C:17]2=[O:22])[CH:15]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Reactant: c1ccoc1
Agent: [I-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Furan (4.0 ml, 55.0 mmol) and magnesium iodide (1.00 g, 3.6 mmol) are added to a solution of 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (5.0 g, 17.9 mmol) in dichloromethane (20 ml) and the mixture is stirred at room temperature for 3 days. A further quantity of furan (1.3 ml, 17.8 mmol) is added and stirring continued for 18 hours, and then a further quantity of furan (1.3 ml, 17.8 mmol) is added and the mixture is stirred for 48 hours, and then allowed to stand at room temperature for 5 days. The reaction mixture is dissolved in methanol and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C#N
Temperature: 50 °C

Procedure:
The 2-fluoro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.59 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq) in isopropanol (10 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give e as a white solid (0.84 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.23 (s, 3H), 1.34 (s, 3H), 4.99 (m, 1H), 7.44 (m, 2H), 8.01 (d, 1H, J=8).