Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:28][CH:29]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)c1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
Platinum(IV) oxide (15 mg) was added to a mixture of 9-{4-[4-(1,1-difluoroethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (300 mg) in THF (dry) (10 mL) and MeOH (10 ml). The mixture was stirred at room temperature under hydrogen overnight. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (77.7 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)[CH:6]=CC=1)#N.O.[C:20]([OH:23])(=[O:22])[CH3:21]>Cl>[CH:16]([C:14]1[N:15]=[C:11]([CH:10]=[CH:9][C:5]2[CH:6]=[C:21]([CH:1]=[CH:3][CH:4]=2)[C:20]([OH:23])=[O:22])[S:12][CH:13]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1csc(C=Cc2cccc(C#N)c2)n1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC(C)c1csc(C=Cc2cccc(C(=O)O)c2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
2-(2-(3-Cyanophenyl)ethenyl)-4-isopropylthiazole prepared in Synthetic Example (2.54 g, 10.0 mmol) was dissolved in a mixed solvent of acetic acid (5 ml) and concentrated hydrochloric acid (10 ml) and the resulting mixture was heated under stirring at 100° C. for 4 hours. After water was added, the reaction mixture was extracted with ethyl acetate and dried. The solvent was distilled out to afford the indicated compound (2.51 g) with a yield of 92%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([C:30]#[N:31])=[CH:27][CH:28]=3)[C:23]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=3)=[N:22][N:21]=2)[CH2:16][CH2:15]1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:42][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[O:40][CH3:41])[CH2:33][NH:32][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:47]3[C:46](=[O:48])[C:45]4=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]4[C:43]3=[O:53])[CH2:15][CH2:16]2)=[N:21][N:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C#N)cc23)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(N3CCC(N4C(=O)c5ccccc5C4=O)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 4 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
Then, 30 ml solution of 3.48 g diethyl azodicarboxylate in tetrahydrofuran was added to 100 ml solution of 4.2 g 1-(4-hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 2.94 g phthalimide, and 5.24 g triphenylphosphine in tetrahydrofuran over 30 min under ice-cooling, and then it was stirred at 4° C. for 24 hr. The reaction solution was evaporated, water and ethyl acetate were added thereto, and then the insoluble matters were removed by filtration. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography to give 4.85 g of 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-phthalimidopiperidino)phthalazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:41])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](Cl)(=[O:38])=[O:37])=[C:20]1[CH3:40]>ClCCl>[CH3:15][O:16][C:17](=[O:41])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](=[O:38])(=[O:37])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:20]1[CH3:40]
Reactant: Nc1ccccc1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of aniline (0.022 mL), triethylamine (0.051 mL) and dichloromethane (0.5 mL) was treated with [3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.10 g), and resulting mixture was stirred at room temperature for 4 days. The mixture was diluted with dichloromethane, washed with water and concentrated under reduced pressure to afford the title compound as a colourless gum (0.078 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([F:13])[C:8]([CH2:9][OH:10])=[C:7]([Cl:14])[CH:6]=1)[CH:2]=[CH2:3].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([F:13])[C:8]([CH2:9][O:10][C:28]([N:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]2[CH2:31][CH3:32])=[O:29])=[C:7]([Cl:14])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: C=CCOc1cc(F)c(CO)c(Cl)c1
Product: C=CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 87 %

Procedure:
This compound was prepared from 4-allyloxy-2-chloro-6-fluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (405 mg; 87%); MS (ISP): 474.4 (M+NH4)+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[N:36]=2)[N:33]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([N:34]=[C:35]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)OC(=O)c1nc2ccc(Cl)nn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
653 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 10 ml of N,N-dimethylformamide; 88 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 1.5 hours. To the reaction mixture, 483 mg of isopropyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylate was added under ice cooling conditions, followed by stirring at constant temperature for 3.5 hours. Ice water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected and concentrated; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 462 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2nc(Cl)ncc2F)c1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: CCN(CCCN)Cc1cccc(-c2nc(NCCc3ccc(O)c(Cl)c3)ncc2F)c1

Procedure:
Intermediate 78 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 458. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.28 (d, 1H), 8.17 (s, 2H), 7.66 (m, 2H), 7.17 (d, 1H), 6.97 (d, 1H), 6.78 (d, 1H), 4.48 (s, 2H), 3.59 (t, 2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.79 (t, 2H), 2.06 (m, 2H), 1.36 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13]I)[CH2:11][C@H:10]([CH2:15][CH2:16][C:17]2([CH3:22])[O:21][CH2:20][CH2:19][O:18]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][C@H:10]([CH2:15][CH2:16][C:17]2([CH3:22])[O:18][CH2:19][CH2:20][O:21]2)[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CC[C@H]2C[C@@H](CI)N(Cc3ccccc3)C2=O)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1Cc1ccccc1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 11-5 (900 mg, 6.26 mmol) and HMPA (30 mL) was added NaBH4 (156 mg, 4.20 mmol). After 45 minutes, the reaction was poured into 50 mL 1:1 Et2O/hexanes and then washed with H2O, brine, dried (MgSO4) and concentrated to provide 11-6 as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([NH2:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([NH2:13])=[O:12]
Reactant: NC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1cccc(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluorophenol (5.61 g, 50.0 mmol), 2-bromoacetamide (7.59 g, 55.0 mmol) and K2CO3 (13.82 g, 100 mmol) in acetone (80 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid. (7.89 g, 93%)
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O[CH2:20][N:21]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:27]([N:21]1[CH2:22][CH:6]2[CH:7]([C:2]([CH3:1])([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:3][CH2:4][C:5]2=[O:8])[CH2:20]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC1(c2ccccc2)C=CC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccccc2)CCC(=O)C2CN(Cc3ccccc3)CC21
Reaction time: 0.5 h

Procedure:
To a solution of 14.5 g of 4-methyl-4-phenylcyclohex-2-enone and 24.45 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 65 cm3 of dichloromethane are added, at a temperature of 25° C., 3 drops of trifluoroacetic acid. The reaction mixture is stirred at this temperature for 30 minutes and then heated to reflux for 2 hours. After cooling, 10 g of potassium carbonate are added, the mixture is stirred for 15 minutes and the solution is then filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 5 cm, height 39 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 100 cm3 fractions. Fractions 8 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 9 g of (3aRS,7SR,7aRS)-2-benzyl-7-methyl-7-phenyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1CN(c2ccccn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 48 h
Yield: 46.9 %

Procedure:
To a solution of tert-butyl (2S)-2-methylpiperazine-1-carboxylate (8 g, 39.94 mmol) in DMSO (25 ml) was added 2-bromopyridine (6.594 g, 41.74 mmol), and DIEA (15.48 g, 119.78 mmol). After stirring 2 days at 120° C., the resulting solution was quenched by the addition of DCM (200 ml), washed with water (3×300 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford (S)-tert-butyl 2-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate as a red oil (5.2 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10](OCC)[CH:11]=C=O)=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1.Cl.O1CCOCC1.[C:34](=[O:37])(O)[O-:35].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:34]([OH:35])=[O:37])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: CCOC(C=C=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)O

Procedure:
10.8 Parts of 2-[2,4-dichloro-5-(1-ethoxy-carbonylethoxy)-phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one, 20.6 parts of concentrated hydrochloric acid (38%) and 175 parts of dioxane were combined and heated to 80° for 30 hours. After cooling the solution was poured into 750 parts of water. The pH of the solution was raised to 8-9 by addition of solid sodium bicarbonate. The aqueous solution of the product was then extracted three times with 250 parts of methylene chloride. The organic extracts were discarded. The aqueous solution of the product was then acidified to pH 1 by addition at concentrated hydrochloric acid (38%). The aqueous solution of product was extracted three times with 250 parts of methylene chloride. The solution of product was dried with anhydrous sodium sulfate. The solvent was removed on a rotary evaporator at reduced pressure. The glassy residue was triturated with ether. 4.4 Parts of white solid with m.p. 183°-185° were obtained.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:22])[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>>[ClH:1].[ClH:1].[CH3:3][O:4][C:5](=[O:22])[CH2:6][CH2:7][N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)[CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCNC1CCN(Cc2ccccc2)CC1
Reactant: O=CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)CCN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]-β-alanine methyl ester dihydrochloride, phenylacetaldehyde and sodium cyanoborohydride.
Reaction SMILES: Br[CH:2]([CH3:11])[CH2:3][CH2:4][C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[CH3:11][CH:2]([CH2:3][CH2:4][C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[C:12]#[N:13]
Reactant: Cc1ccc(CCC(C)Br)o1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(CCC(C)C#N)o1
Reaction time: 16 h

Procedure:
A solution of 2-(3-bromobutyl)-5-methyl-furan (20.5 g) and 13 g KCN in 100 ml of dry dimethyl sulphoxide was heated during stirring for 16 hours at 50°-55° C. The mixture was cooled, diluted with water and extracted using ether. The extracts were washed with water, dried on anhydrous MgSO4 and boiled down under vacuum. The residue was subjected to chromatographic adsorption over silicagel with hexane/ethyl acetate (9:1) and gave 14.6 g dl-2-methyl-4-(5-methyl-2-furyl)-butane nitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:27]3[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:25]([C:24]([F:23])([F:39])[F:38])[CH:26]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)o2)c1
Temperature: 100 °C

Procedure:
The furyl bromide (99) (70 mg, 0.19 mmol) was coupled to 3,5-bis-trifluoromethyl-phenylboronic acid (55 mg, 0.21 mmol) acid using Method E, except that the reaction was heated at 100° C. The crude product was purified by column chromatography eluting with a stepped gradient of 0-10% EtOAc in heptane to give the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:20]=[N:19][CH:18]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:21]2[CH:20]=[N:19][CH:18]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[N:22]=2)[CH2:24]1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(c2cncc(Cl)n2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1occc1-c1cncc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (567 mg, 2.72 mmol) was added to a solution of cis-4-(6-chloro-2-pyrazinyl)-2,6-dimethylmorpholine (620 mg, 2.72 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (577 mg, 5.45 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (315 mg, 0.272 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 1 hour. Crude LCMS shows desired product and starting material so the reaction mixture was stirred and heated for a further 1 hour at 100° C. in the microwave. Crude LCMS shows desired product and no starting material can be seen. The reaction mixture washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜5 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (441 mg, 1.533 mmol, 56.3% yield). LC/MS [M+H]+=274.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCC1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To 300 ml. of DMF were added 107 grams of phenyl p-hydroxybenzoate and 26 grams of sodium hydride (50 percent in oil). The mixture was heated at 60° C. for two hours. To the mixture then were added 67 grams of 1-chloro-2-pyrrolidinoethane, and the mixture was stirred overnight at 85° C. The bulk of the DMF then was evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated, and the residue was dissolved in a 1:1 mixture of ether and ethyl acetate. The organic solution then was extracted with 2 N hydrochloric acid, and the acid extract was added dropwise to 2 N sodium hydroxide. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and then dried over magnesium sulfate. The ethyl acetate was concentrated to obtain 110 grams of crude phenyl p-(2-pyrrolidinoethoxy)benzoate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:22]([C:24]1[C:29](Br)=[N:28][CH:27]=[CH:26][N:25]=1)=O.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[CH3:22][C:24]1[C:29]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:28][CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)c1nccnc1Br
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nccnc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 97 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 3-bromo-pyrazin-2-carboxylic acid methyl ester followed by reduction with lithium tri-sec-butylborohydride at 0° C. in THF: MS (m+1)=375.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18]C=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:24][O:25][C:26]1[CH:31]=C(NN)C=C[N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:27]=[C:26]([O:25][CH3:24])[CH:31]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(NN)ccn1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: COc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
500 mg (1.53 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 295 mg (1.68 mmol) of 2-methoxypyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 8 mg (1.5% of theory) of the title compound is obtained.