Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]#[N:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.[OH-:16].[Na+].OO>CS(C)=O.C(OCC)(=O)C.O>[CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:16])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CSc1nc(NC2(C)CC2)ncc1C#N
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1nc(NC2(C)CC2)ncc1C(N)=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
To a stirring solution of 2-(1-methylcyclopropylamino)-4-(methylthio)pyrimidine-5-carbonitrile (0.653 g, 2.96 mmol, synthesis described herein) in DMSO (8 mL) was added 6N aqueous sodium hydroxide (2.470 mL, 14.82 mmol) solution and 30% aqueous hydrogen peroxide solution (1.873 mL, 16.52 mmol) at 0° C. Then the mixture was stirred at 50° C. and for 20 minutes and was then diluted with 100 mL ethyl acetate and 30 mL water. The layers were separated and the aqueous layer was back extracted with 50 mL ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated to solids that were dried in a vacuum oven at 45° C. to afford 2-(1-methylcyclopropylamino)-4-(methylthio)pyrimidine-5-carboxamide (305 mg, 1.280 mmol, 43.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31-8.54 (m, 1H), 7.80-8.07 (m, 1H), 6.97-7.77 (m, 1H), 2.39 (br. s., 3H), 1.37 (s, 3H), 0.52-0.79 (m, 4H). MS (ESI) m/z 239.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([S:56][CH2:57][CH2:58]CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:58][CH2:57][S:56][C:53]2[CH:54]=[CH:55][C:50]([CH3:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccc(SCCCO)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 71.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (121 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[(4-methylphenyl)sulfanyl]-1-propanol (74 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (98 mg, yield 67%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:24]([O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25]>ClCCl>[CH:39]1[C:40]2[CH:28]([CH2:27][O:26][C:24]([NH:12][C@H:4]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[C:3]([O:2][CH3:1])=[O:13])=[O:25])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]=2[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)C(N)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° solution of 2.50 g (11.48 mmol) of amino-(4-hydroxy-phenyl)-acetic acid methyl ester (from Example 178) in 125 mL of dichloromethane was added 10 mL of N,N-diisopropylethylamine followed by 2.97 g (11.48 mmol) of 9-fluorenylmethyl chlorformate and the resulting mixture was stirred at 0° for 2 h and room temperature for 2 h. The reaction mixture was then concentrated and the residue was diluted with ethyl acetate and water. The organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide methyl(2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}(4-hydroxyphenyl)ethanoate as a white solid. Electrospray Mass Spec 404.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH3:16])[N:8]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1.[C-]#N.[Na+].C1N2CC[N:22](CC2)[CH2:21]1>CS(C)=O.O>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:8]1[C:7]([CH3:16])=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:21]#[N:22])=[N:3][CH:4]=2
Reactant: C1CN2CCN1CC2
Reactant: Cc1nc2cnc(Cl)nc2n1CC(C)(C)C
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cnc(C#N)nc2n1CC(C)(C)C

Procedure:
6.1 g of 2-chloro-9-(2,2-dimethyl-propyl)-8-methyl-9H-purine, 1.25 g of NaCN and 0.57 g of DABCO were heated for 6 hours to 80° C. in 60 ml DMSO/H2O=90:10. The crude mixture was extracted with ethyl acetate and saturated NaHCO3 solution and the organic phases were dried over sodium sulfate and evaporated to dryness. After chromatography on silicagel with ethyl acetate/hexanes=1:1 9-(2,2-dimethyl-propyl)-8-methyl-9H-purine-2-carbonitrile was isolated as a pale brown powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[CH:30](=[O:32])[CH3:31]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:30]([OH:32])[CH3:31])[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (1.3 mL, 9.092 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (10 mL) was treated with a solution of n-butyllithium in hexanes (3.4 mL, 8.524 mmol, 2.5 M). After stirring at −78° C. for 30 minutes, the mixture was treated with a solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (1.394 g, 5.683 mmol) in anhydrous tetrahydrofuran (10 mL). After stirring at −78° C. for 20 minutes, the mixture was treated with acetaldehyde (0.96 mL, 17.05 mmol). After stirring at room temperature for 1 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 40 mL). The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (1.476 g, 90%) as a yellow oil and as a 2:1 mixture of diastereoisomers.
Reaction SMILES: [C:1]12(CS(O)(=O)=O)C(C)(C)C(CC1)C[C:2]2=O.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([OH:28])=[O:27])[NH:17]1>C(O)C.Cl>[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([O:28][CH2:1][CH3:2])=[O:27])[NH:17]1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1Cc2ccccc2CN1
Yield: 103.1 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid camphor sulphonic acid salt (Preparation 120, 6 g, 17.2 mmol) was dissolved in ethanol (140 ml) and saturated with hydrogen chloride (gas). The reaction mixture was heated under reflux for 18 h before concentrating in vacuo. The crude residue was dissolved in dichloromethane (150 ml) and washed with sodium hydrogen carbonate (150 ml). The organic layer was collected and washed again with sodium hydrogen carbonate (2×100 ml) before drying (Na2SO4) and concentrating in vacuo to give the title compound as a yellow oil (3.64 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(=O)CBr)[CH:10]=[CH:9][N:8]=[N:7]1)=[O:5])[CH3:2].[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.[CH2:24](O)[CH3:25].C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:24]2[N:23]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:22][CH:25]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)CBr)C=CN=N1
Reactant: NC(=S)c1cccnc1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2csc(-c3cccnc3)n2)[nH]n1

Procedure:
A mixture of 3-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester (7.00 g), thionicotinamide (3.51 g), and ethanol (50 ml) was refluxed for 16 hours. The resulting mixture was poured into 400 ml of water, and neutralized with 10 g of sodium bicarbonate. Filtration afforded 5.82 g of 3-ethoxycarbonyl-5-(2-(3-pyridinyl)thiazol-4-yl)pyrazole as yellow solids, mp 105°-107° C. NMR: 1.43 (t, 3H), 4.44 (q, 2H), 7.26 (s, 1H, 5-thiazolyl H), 7.70 (s, 1H, 4-pyrazolyl H), 7.42, 8.30, 8.73, 9.27 (4 m, 4H, pyridinyl H's).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[CH3:2].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Temperature: 0 °C
Yield: 48.1 %

Procedure:
To [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester (Example 2, step 2) (48.0 g, 0.11 mol), ethyl bromoacetate (188 g, 1.12 mol) and diisopropylethylamine (145.57 g, 1.12 mol) in DMF (480 mL) were stirred at 120° C. for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to give pure {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonylmethyl-amino}-acetic acid ethyl ester (27.1 g, 47% yield).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30](OCC)(=[O:32])C.CCCCCC>C(Cl)(Cl)Cl>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C@@H:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([O:32][CH3:30])[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: CCOC(C)=O
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 98 %

Procedure:
Using (−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51, the title compound was synthesized in the same manner as in Example 36. Yield: 98%. Melting point: 150-151° C. (ethyl acetate -hexane). [α]D20=+55.9° (c=0.50, chloroform).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[N:13]1[C:18]2[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[NH:22][C:23](=[O:24])[C:17]=2[CH:16]=[N:15][CH:14]=1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:19]1[C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[NH:22][C:23](=[O:24])[C:17]2[CH:16]=[N:15][CH:14]=[N:13][C:18]1=2)=[O:4]
Reactant: O=C1Nc2ccccc2Nc2ncncc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2ncncc21

Procedure:
A solution of 3.16 g (0.028 mol) of chloroacetyl chloride in 8 ml of absolute dioxan and a solution of 2.82 g (0.028 mol) of dry triethylamine in 6 ml of absolute dioxan are added dropwise, simultaneously and as uniformly as possible, in the course of 20 minutes, at 60° to 70° C., to a suspension of 4.24 g (0.02 mol) of 5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 60 ml of absolute dioxan, while stirring. The mixture is heated under reflux for a further 4 hours; precipitated triethylamine hydrochloride is filtered off, and the filtrate is concentrated in vacuo. The residue is chromatographed on neutral silica gel, using chloroform; the eluate is evaporated and the residue therefrom is stirred with ether and, after filtration, recrystallized from ethanol; yield: 3.9 g, m.p. 196° C. (dec.), from isopropanol.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C1COCC1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=3[F:42])[N:30]=[CH:31][C:24]=12>C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=4[F:42])[N:30]=[CH:31][C:24]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.8 g, 45.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.53 g, 7.6 mmol). THF (anhydrous, 80 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 7.6 mmol) was then added in one portion. The mixture was stirred overnight under N2 at room temperature and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Column chromatography purification using 50% EtOAc/Hexane gave Compound A74 as an off-white solid. Exact mass calculated for C22H26FN5O5S: 491.16, found 492.1 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[F:2][C:3]([F:19])([F:20])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH:15][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)Cl
Reactant: NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 4-[3-(trifluoromethyl)phenoxy]phenylhydrazine hydrochloride (11 g) and pyridine (6.0 mL) in ethyl acetate (100 mL) at 0° C. was added dropwise isopropyl chloroformate (38 mL, 1M in toluene) over a period of 30 min. The mixture was then stirred at room temperature for 5 hour, quenched with 1M aqueous HCl (100 mL). The organic layer was separated, washed twice with water (100 mL), dried over anhydrous sodium sulfate, and finally evaporated under reduced pressure to yield a light brown solid (11 g).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:22][C:9]1[C:10]([NH2:20])=[N:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=2)[N:8]=1
Reactant: Cc1ccc(-c2ncc(N)nc2-c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-di-p-tolylpyrazin-2-amine (step 2) (4.94 g, 17.94 mmol) in DMSO (40 ml) was treated with N-bromosuccinimide (3.19 g, 17.94 mmol). The reaction mixture was stirred at room temperature for 2 hours to give a beige coloured suspension. The suspension was diluted with water (700 ml) and the pH was adjusted to pH 8-9 using a sat. NaHCO3 solution. The suspension was filtered, washed with water (×3) and dried under vacuum to afford the titled compound as a beige coloured solid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22])[CH:17]=O>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH:9]=[CH:17][C:16]1[CH:19]=[C:20]([CH3:23])[C:21]([OH:22])=[C:14]([CH3:13])[CH:15]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(Cl)ccc1C(C)=O
Product: COc1cc(Cl)ccc1C(=O)C=Cc1cc(C)c(O)c(C)c1

Procedure:
This compound was synthesized from 4′-chloro-2′-methoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]1[CH3:20])([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.[CH:21]([N:34]1[CH2:39][CH2:38][NH:37][C@@H:36]([CH3:40])[CH2:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(N(CC)CC)C>CC#N>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:16][C@@H:15]1[CH3:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:21]([N:34]1[CH2:39][CH2:38][N:37]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:36]([CH3:40])[CH2:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C[C@H]1CNCCN1C(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CN(C(c2ccccc2)c2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CN(C(c2ccccc2)c2ccccc2)CCN1CC(=O)OC(C)(C)C
Product: C[C@H]1CN(CC(=O)OC(C)(C)C)CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of (S)-1-benzhydryl-2-methylpiperazine and (S)-1-benzhydryl-3-methylpiperazine (490 mg, 1.839 mmol) in 25 mL of MeCN was added tert-butyl bromoacetate (356 μl, 2.207 mmol), followed by slow addition of triethylamine (384 μl, 2759 μmol). The reaction mixture was stirred at rt overnight. The solution was evaporated to dryness and the residual was submitted to flash chromatography (SiO2, DCM to DCM/EtOAc=100:3 to 100:5 to 100:10) to give (S)-tert-butyl 2-(4-benzhydryl-3-methylpiperazin-1-yl)acetate as a colorless oil and (S)-tert-butyl 2-(4-benzhydryl-2-methylpiperazin-1-yl)acetate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2cc(OC)ccc2C1=O
Yield: 31 %

Procedure:
A solution of 50.0 g of 5-methoxy-1-indanone, 80 ml of 3-buten-2-ol, 132 ml of 2,2-dimethoxypropane and 600 mg of p-toluenesulfonic acid in 500 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux for an additional 48 hours. After cooling, the solution was evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 19.2 g (31%) of (RS)-2-(2-buten-1-yl)-5-methoxy-1-indanone as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[NH:6][C:5]2=[O:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C(O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:7][N:6]2[C:5](=[O:12])[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:24][C:23]4[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=4)[CH:3]=3)[C:13]2=[O:16])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2cc(O)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccc(OCc3ccc(F)cc3)cc2C(=O)N1Cc1ccc(F)cc1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
A mixture of 5-hydroxy-isoindole-1,3-dione (200 mg, 1.0 mmol), potassium carbonate (178 mg, 1.05 mmol), 4-fluorobenzylbromide (204 mg, 1.05 mmol) in ethanol (5 mL) was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, heptane-CH2Cl2 2:3 then CH2Cl2— 2N NH3-MeOH 99:1: to 95:5) to afford the title compound (13 mg, 3%) as a white solid. MS: m/e=379.4 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH3:21].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:25]2[N:24]=[N:23][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.58 mmol, 0.126 g) in DMF (1.0 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (1.74 mmol, 0.07 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.29 mmol, 0.10 g) in DMF (0.5 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 12 hour. The reaction was poured into a mixture of water (10 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using ethyl acetate/hexanes gradient to give 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester.