Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]([C:34](=[O:43])[CH2:35][CH2:36][C:37]([CH3:42])([CH3:41])[C:38]([OH:40])=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:44].O1CCOCC1>>[ClH:44].[CH3:42][C:37]([CH3:41])([CH2:36][CH2:35][C:34]([N:24]1[CH2:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:23]1)=[O:43])[C:38]([OH:40])=[O:39]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)CCC(C)(C)C(=O)O)CCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(C(=O)CCC(C)(C)C(=O)O)CCC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 225 mg of the crude 5-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-2,2-dimethyl-5-oxopentanoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution 2.0 mL, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in THF. Diisopropylether was added dropwise thereto, and the precipitate was isolated by filtration. This was dried under reduced pressure at 50° C. to obtain 170 mg of 2,2-dimethyl-5-[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-5-oxopentanoic acid hydrochloride as a white solid.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C>FC(F)(F)C1C=C(C2NC(=O)N(C3CCNCC3)C=2)C=C(C(F)(F)F)C=1.CN(C)C=O>[C:22]1([CH2:21][O:20][C:18]([NH:1][C@H:2]([C:15]([N:69]2[CH2:70][CH2:71][N:66]([C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)[CH2:67][CH2:68]2)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=c1[nH]c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol) of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of 15 dimethylformamide were added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml (0.268 mol) of DIEA with stirring and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate and aqueous saturated sodium hydrogen carbonate solution. The aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution. The organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 3% aqueous ammonia solution and twice with 100 ml of water. The organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:25]([C:24]3[CH:28]=[C:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=[CH:31][C:23]=3[O:22][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1(b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH2:21])(=[O:11])=[O:10])#[N:2].[ClH:26].N1C=CC([C:32]([NH2:34])=[NH:33])=N1>CN(C)C=O>[ClH:26].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH:21][C:32]([NH2:34])=[NH:33])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2C#N)c1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
To a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyamine (362 mg, 1.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide (10 mL) was added 1H-pyrazole-carboxamidine hydrochloride (590 mg, 4.0 mmol). The reaction mixture was stirred at ambient temperature for two days. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile (10 mL) was added, the solid was removed by filtration, the filtrate was concentrated in vacuo, and the residue was dried under high vacuum. The residue was partitioned between water (30 mL plus 2 mL brine) and diethyl ether (20 mL). The water solution was extracted with diethyl ether (20 mL), and the combined diethyl ether extracts were extracted with acidic water (pH 5). The combined water solutions were adjusted to pH 8-9 by using 2N NaOH and extracted with ethyl acetate (3×50 mL). The ethyl acetate solution was washed with pH 7 buffer solution (2×30 mL) and brine (30 mL) and dried over Na2SO4. After removing the solvent, 0.6N HCl methanol (10 mL) was added, and the solution was concentrated to give the title compound as a colorless oil (340 mg, 77%). 1H-NMR (300 MHz, DMSO-d6) δ8.30 (d, J=7.5 Hz, 1H), 8.09 (t, J=7.5 Hz, 1H), 8.04 (m, 2H), 7.72 (br s, 5H), 6.79 (s, 1H), 6.49 (s, 1H), 6.47 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 2.22 (s, 3H), 2.01 (m, 2H). Mass spectrum (MALDI-TOF, (α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H20N4O5S: 405.1 (M+H), 427.1 (M+Na). Found: 405.1, 427.0.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[N:43][CH:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:46]=[CH:45][N:44]=[N:43][CH:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccnnc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccnnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyridazine-4-carboxamide
Reaction SMILES: [C:1](=[O:34])(OC1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH3:35][N:36]1[CH:40]=[C:39]([S:41]([NH2:44])(=[O:43])=[O:42])[N:38]=[CH:37]1>>[Cl:24][C:17]1[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:34])[NH:44][S:41]([C:39]4[N:38]=[CH:37][N:36]([CH3:35])[CH:40]=4)(=[O:43])=[O:42])=[CH:10][CH:9]=3)[C:15]=2[CH:16]=1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cn(C)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 1-methyl-1H-imidazol-4-ylsulfonamide.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[O:15]C(=O)N)([CH2:3][CH3:4])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[OH:15])([CH2:13][CH3:14])[CH3:12]
Reactant: CCC(C)c1cccc(C(C)CC)c1OC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(C)c1cccc(C(C)CC)c1O
Yield: 100.3 %

Procedure:
R-(+)-1-Phenyl-ethyl)-carbamic acid (−)-2,6-di-sec-butylphenyl ester (1b) (4.1 g, 11.6 mmol) was dissolved in a 100 ml 1:1 mixture of dioxane: 1M NaOH aq. The reaction mixture was stirred at 70° C. for 15 min. Volatiles were removed at reduced pressure to a volume of ˜50-70 ml. The pH was adjusted to 3-4 with 1M HCl. The phenol was extracted with ether (3×50 ml), washed with 1 M HCl, brine and dried over anhydrous MgSO4. Evaporation yielded crude yellow oil (2.4 g, ˜100%). Vacuum distillation was performed (120-125° C./˜5 mm) (2.1 g, 89%). Optical rotation: α20D=−14.11° (c=2, pentane).
Reaction SMILES: C([N:3](CC)CC)C.FC(F)(F)S(O[C@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)=O>ClCCl>[NH2:3][C@H:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:22]
Reactant: C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-nitrophenylalanine, ethylester, hydrochloride (2.3 g) in dichloromethane (10 ml), add triethylamine (2.55 ml) and then t-butyl 2(R)(trifluoromethanesulfonyloxy)propionate (2.80 g) (see Preparation 4) in dichloromethane (10 ml). Stir the resulting solution at room temperature for 20 hours. Concentrate the reaction mixture, add diethyl ether and extract with salt solution. Dry over magnesium sulfate and concentrate the ether solution in vacuo to give an oil. Place the oil on a column of silica gel (100 ml, 60-200 mesh) and elute with diethyl ether:hexane 60:40 to give N-[1(S)-ethoxycarbonyl)-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl ester.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[O:10][CH:11](C2C=CC=CC=2)[CH:12]2[CH:16]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]([O:26][CH3:27])[CH:14]([N:28]3[CH:36]=[N:35][C:34]4[C:33](=[O:37])[NH:32][C:31]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[N:30][C:29]3=4)[O:13]2)=CC=1.C(O)=O.C(O)CCC>C(Cl)Cl.CO>[OH:10][CH2:11][CH:12]1[CH:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]([O:26][CH3:27])[CH:14]([N:28]2[CH:36]=[N:35][C:34]3[C:33](=[O:37])[NH:32][C:31]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])=[N:30][C:29]2=3)[O:13]1
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)C(OC)C2OC(=O)c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: CCCCO
Solvent: ClCCl
Product: COC1C(OC(=O)c2ccccc2)C(CO)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Yield: 115.7 %

Procedure:
Compound 16.4 (1.5 g, 1.54 mmol) was dissolved in a mixture of 8 mL CH2Cl2 and 8 mL methanol, and treated with formic acid 16 mL. When the reaction was completed, 20 mL n-butanol was added to quench the reaction. The mixture was evaporated to dryness under reduced pressure and the byproducts were removed by washing the residue with hexane 3×200 mL. Compound 16.5 (840 mg, 92% yield) was obtained.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>>[C:2]1([C:1]2[O:8][C:1]([C:2]3[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=3)[C:16]([OH:17])=[O:19])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cccc(-c2nnc(-c3ccccc3)o2)c1
Temperature: 120 °C

Procedure:
A mixture of methyl hydrogen isopthalalate (1.8 g, 10 mmol), benzoic hydrazide (1.4 g, 10 mmol) and phosphorous oxychloride (20 ml), under an atmosphere of nitrogen, was heated at 120° C. for 18 hours, then cooled to room temperature and then poured into ice water (500 ml). This mixture was treated with solid sodium carbonate until the aqueous layer was basic (pH 8-9) and the resultant pink solid was filtered. This material was treated with 100 ml methanol and the suspension was treated with sodium hydroxide solution (30 ml, 1M). The reaction mixture was heated at reflux for 4 hours, then cooled and then concentrated to dryness. The residue was dissolved in water (100 ml) and the solution was acidified to pH 3 by addition of concentrated hydrochloric acid. The resultant precipitate was filtered, then dried and then subjected to chromatography on silica gel eluting with a mixture of dichloromethane and methanol (98:2, v/v) to yield 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-benzoic acid as a white solid (600 mg). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.80 (s, 1H), 8.38 (m, 1H), 8.18 (m, 3H), 7.78 (m, 1H), 7.62 (m, 3H). MS(EI): 265(M+−H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)[CH:16]=[CH:17][CH:18]=1.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C=Cc1cccc(OCc2ccc3ccccc3n2)c1)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A solution of 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)phenol (0.008 mol) in ethyl acetate (150 ml) is shaken under 50 psi of hydrogen gas in the presence of 10% palladium an carbon catalyst (1.0 g). The reactionis filtered through a celite pad and evaporated to give 4-(3-(3-(2-quinolinylmethyloxy)phenyl)propyl)phenol.
Reaction SMILES: O[CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].O[Li].O>C(O)=O.[Zn]>[OH:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:8]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:29])[C:13]1=[O:28]
Reactant: Cc1cncc(Oc2cnc3c(c2C(O)CC(C)C)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: [Li]O
Agent: [Zn]
Solvent: O=CO
Solvent: O
Product: Cc1cncc(Oc2cnc3c(c2CCC(C)C)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.04 mmol) in HCOOH (2 mL) was added Zn dust (64 mg, 0.375 mmol). The reaction was heated at 100° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated, dried to a residue then dissolved in THF (1 ml) and water (1 mL). Next LiOH.H2O (33.6 mg, 0.8 mmol) was added and the reaction was stirred at RT for 10 min then extracted with EA (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(5-methylpyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 mg, 7% yield) as clear oil. 1H NMR (CDCl3) δ: 8.29 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 6.99 (s, 1H), 4.26 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (d, J=18.8 Hz, 2H), 3.33-3.23 (m, 2H), 3.20 (s, 1H), 2.33 (s, 3H), 1.99-1.92 (m, 2H), 1.68 (dt, J=11.9, 6.0 Hz, 1H), 1.40 (dt, J=10.7, 6.8 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H). LCMS: MH+ 413 and TR=2.549 min.
Reaction SMILES: ClC1C(Cl)=CC=CC=1C1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[Na+].[I-].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1CCNCC1.CCN(C(C)C)C(C)C>CC#N>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Clc1cccc(C2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCOc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of intermediate 44 (42.2 mg, 0.17 mmol) and NaI (49.5 mg, 0.33 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 65 (35.0 mg, 0.18 mmol), followed then by DIEA (0.063 mL, 0.36 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-1H-indazole (compound 50) (36.6 mg, 60%). HPLC: 99%, RT 3.907 min. MS (ESI) m/z 367.20 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[O:39])[CH:34]=[CH:35][CH:36]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2.0 g, 0.005 mol) in 15 ml of methylene chloride is added a solution of m-chlorophenyl isocyanate in 10 ml of methylene chloride at 0° C. under nitrogen. The resulting suspension is stirred for 1 hour at room temperature. The above mixture is then filtered and the white solid residue is washed with more methylene chloride and dried. This is recrystallized from methanol/methylene chloride to give 2.5 g (90%) of white crystalline 1-[[(3-chlorophenyl)amino]carbonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 266°-268° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](Cl)=[N:7][C:6]([Cl:13])=[N:5][C:4]=2[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][C:6]([Cl:13])=[N:5][C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ncc(Br)cc2n1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
To an ice cold solution of crude 7-bromo-2,4-dichloro-pyrido[3,2-d]pyrimidine (2.85 g, 0.0102 mol) in DCM (25 mL) at 0° C. was added morpholine (1.8 g, 0.0204 mol). The reaction was continued at 0° C. for 30 min. The volatiles were evaporated and subjected to column chromatography (60-120 silica gel, 0-12% ethyl acetate in hexane) to get the title compound as a light yellow solid [0.35 g, 26%]. 1H NMR (300 MHz, DMSO-d6): δ 8.68 (d, J=2.7 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 3.86-3.89 (m, 8H); LC-MS (ESI): Calculated mass: 328.0; Observed mass: 330.8 [M+H]+ (RT: 1.50 min).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3Br)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccn1
Reactant: OB(O)c1cccnc1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4cccnc4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “8” by using 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine and 3-pyridinylboronic acid as the starting materials. LC-MS (M+H=524, obsd=524). 1H NMR (400 MHz, DMSO-d6) δ 8.59-8.50 (m, 2H), 8.38 (dd, J=5.1, 0.8 Hz, 1H), 8.11 (s, 1H), 7.80-7.72 (m, 2H), 7.53-7.47 (m, 2H), 7.43 (dd, J=5.1, 1.6 Hz, 1H), 5.92 (s, 2H), 3.85 (t, J=6.1 Hz, 2H), 3.40-3.27 (m, 5H), 3.63 (d, J=3.1 Hz, 1H), 3.12 (s, 5H), 3.01 (p, J=6.9 Hz, 1H), 2.85 (dt, J=10.1, 5.0 Hz, 1H), 2.77-2.63 (m, 4H), 2.01-1.87 (m, 2H), 1.65-1.52 (m, 4H), 1.25 (d, J=6.9 Hz, 6H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][CH:31]=[C:30]([OH:38])[CH:29]=1>>[OH:37][CH:34]([C:33]1[CH:32]=[CH:31][C:30]([OH:38])=[CH:29][CH:28]=1)[CH2:35][NH:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)c1ccc(O)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)cc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-octopamine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 2.00–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.60–3.70 (m, 2 H), 4.80–4.90 (m, 1 H), 6.00 (brs, 1 H), 6.76 (d, J=9.7 Hz, 2 H), 6.80 (d, J=9.7 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.19 (d, J=8.7 Hz, 2 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70 (d, J=8.7 Hz, 2 H), 9.47 (s, 1 H), 10.43 (s, 1 H); MS (ES) m/z: 525.3 (MH+); HRMS Calcd. for C27H33N4O5S (MH+): 525.2172. Found: 525.2178.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccc1
Product: O=Cc1ccc(Oc2ccccc2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and phenol.