Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[N:21]1>>[S:20]1[CH:24]=[C:23]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[N:22]=[N:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1csnn1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4csnn4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with thiadiazole-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(thiadiazol-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:19])=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12]([Cl:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCC(C(=O)O)c1ccc(CC(C)C)cc1
Product: CCC(C(=O)Cl)c1ccc(CC(C)C)cc1
Yield: 98.1 %

Procedure:
110 g of 2-(4-isobutylphenyl)butyric acid and 89 g of thionyl chloride are heated on a water bath until the gas evolution ceases. An excess of thionyl chloride is removed by distillation, A residue of 117 g of 2-(4-isobutylphenyl)butyric chloride is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:58]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]6)=[O:49])=[CH:44][C:43]=5[CH3:58])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)c2ccc(Br)c(C)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(C)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (162 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-(4-ethyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-146) as a pale yellow powder (25 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:22](OC(C)(C)C)(=[O:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH2:10][C:22](=[O:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h

Procedure:
To a solution of the product from step B (4.1 g, 21.7 mmol) in 100 mL of diethyl ether at −78° C. was added lithium bis(trimethylsilyl)amide (23.9 mL, 23.9 mmol). After 50 min at −78° C. di-tert-butyl oxalate (4.18 g, 20.66 mmol) was added as a solid. The cold bath was removed and after 2 h an additional portion of di-tert-butyl oxalate (530 mg, 2.6 mmol) was added and stirring continued at ambient temperature for 16 h. The reaction was quenched by adding 150 mL of 1N hydrochloric acid and stirring for 1 h. The mixture was extracted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as an oil which was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.84 (d, J=1.9 Hz, 2H); 7.59 (d, J=1.9 Hz, 1H); 6.93 (s, 1H); 1.56 (s 9H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:4]=[N:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:8]=1)(=[O:16])[CH3:15]
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(-c2cncnc2)c1
Yield: 82 %

Procedure:
2b is acetylated with acetic anhydride to afford 2c (15.4g, 82%). Mp 157-158° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[S:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][C:18]=1[Cl:19]>>[Cl:19][C:18]1[CH:17]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[S:15][C:14]=1[Cl:13]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Cl)c(Cl)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,3-dichlorothiophene-5-sulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (36.9 mg) with purity >90%. MS (pos) m/z 401.1, 403.1.
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([CH:11]=[C:12]2[S:16][C:15](SC)=[N:14][C:13]2=[O:19])=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1>CN(C=O)C>[CH:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([CH:11]=[C:12]2[S:16][C:15]([N:26]3[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]3)=[N:14][C:13]2=[O:19])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CSC1=NC(=O)C(=Cc2ccc(Oc3ccccc3C(C)C)cc2)S1
Reactant: O=C(O)C1CNC1
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Oc1ccc(C=C2SC(N3CC(C(=O)O)C3)=NC2=O)cc1

Procedure:
was prepared from 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid and substituting MeCN with DMF as described in Example 5C
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]([O:27][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:13][CH2:14]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccccc1N1CCN(CCc2ccc(O)c3ncccc23)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCc2ccc(OC(=O)C(C)(C)C)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 7.27 g of 5-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-8-hydroxy quinoline in 150 ml of anhydrous tetrahydrofuran in the presence of 3.1 ml of triethylamine and 5 ml of pivaloyl chloride is stirred for 48 hours at room temperature. After evaporation of the tetrahydrofuran, the residue is taken up in chloroform and washed with a 10% NaHCO3 solution. After evaporation of the chloroform, a crystalline residue is obtained which is recrystallised in 80 ml of isopropanol. Finally, 6.45 g of 5-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-8-pivaloyloxy quinoline are obtained melting at 115° C.
Reaction SMILES: Cl.CO[CH:4]([O:21]C)[CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8]>CC(C)=O>[OH:21][CH:4]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][C:16]=3[CH:17]=[C:9]2[C:7](=[O:8])[NH:6][CH2:5]1
Reactant: COC(CNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=C1NCC(O)n2c1cc1cc([N+](=O)[O-])ccc12
Yield: 97 %

Procedure:
HCl 2N (13.75 ml, 27.5 mmol, 2.5 eq.) was added to a solution of the compound of formula (IV) (3 g, 11 mmol, 1 eq.) in acetone (200 ml), the final solution was stirred at 25° C. for 48 h. The solution was dried under reduced pressure affording the compound of formula (V) as yellow solid that was used in the subsequent step without further purification. Same procedure on 30 g scale proceeded smoothly. Typical yield: 97%.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH3:18])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.[N:32](OCCC(C)C)=O>C(Cl)(Cl)Cl>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]([CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:2](=[N+:1]=[N-:32])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1)[CH3:18]
Reactant: COC(=O)C(N)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]

Procedure:
A mixture of methyl 2-amino-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]propanoate (5.00 g), acetic acid (4.4 mL) and chloroform (160 mL) was treated dropwise with isoamyl nitrite (3.2 mL). The mixture was heated at reflux for 1.5 hrs, cooled, diluted with chloroform (200 mL) and washed successively with dilute hydrochloric acid (200 mL), water (2×200 mL) and brine (200 mL). The chloroform solution was dried over MgSO4, evaporated and the residue chromatographed on silica gel using 3% ethyl acetate in dichloromethane as eluent to afford the title compound, a gum.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8](COC)[C:7]=2[CH:19]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:19]=1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: ClCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
Into 250 ml of a solution of 26.9 g of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in methylene chloride was dropped 50 ml of trifluoroacetic acid at 0° C. After reacting at room temperature for 12 hours, the reaction mixture was cooled to 0° C. and neutralized by adding an aqueous solution of sodium hydrogencarbonate. The crystals thus precipitated were taken up by filtration and washed successively with water and diethyl ether to thereby give 19.1 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].O=[C:26]1[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:29]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[C@@H:28]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:27]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[C:26]1[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:29]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@@H:28]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:27]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To an oven-dried 25 mL round-bottomed flask equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed methyl (triphenylphosphoranylidene) acetate (199 mg, 0.597 mmol) and toluene (5 mL). To this heterogeneous solution was added a solution of 1,2-dibenzyl 3-tert-butyl (2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate (93 mg, 0.199 mmol) in toluene (3 mL). The reaction mixture was heated to reflux and stirred overnight. The volatiles were then removed in-vacuo and the yellow oil was purified by Combiflash (10 to 30% ethyl acetate in hexanes) to afford 83 mg (80%) of 1,2-dibenzyl 3-tert-butyl (2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate. LCMS (ESI): 424 (M-CO2t-Bu+2H+), 468 (M−t-Bu+2H+), 524 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:34]6[N:35]=[CH:36][CH:37]=[CH:38][N:33]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2ncccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.074 g, 0.55 mmol, 1.2 eq), HOBT (0.105 g, 0.77 mmol, 1.7 eq), EDC.HCl (0.0.158 g, 0.82 mmol, 1.8 eq), in DCM at ambient temperature and under nitrogen atmosphere was added diisopropylehtylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.055 g (45%). 1HNMR (400 MHz, DMSO-d6): δ 1.43-1.44 (m, 2H), 1.59-1.62 (m, 2H), 2.31 (s, 3H), 2.81-2.82 (d, 3H, J=4.56 Hz), 4.01 (s, 3H), 7.17 (s, 1H), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.33-7.36 (dd, 1H, J=8.4, 4 Hz), 7.38-7.43 (t, 2H, J=8.8 Hz), 7.50-7.51 (d, 1H, J=1.6 Hz), 7.72-7.76 (m, 2H), 7.97-8.01 (m, 2H), 8.48-8.49 (d, 1H, J=4.4 Hz), 8.7 (d, 2H, J=4.8 Hz), 8.87 (s, 1H). LCMS: (ES+) m/z=551.2 (M+H) Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [CH3:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10]C1C=CC(C)=CC=1O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:10])[CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: Cc1ccc(C)c(O)c1
Reactant: Cc1cccc(O)c1C
Product: Cc1ccc(O)c(C)c1

Procedure:
2,3-dimethylphenol; 2,5-dimethylphenol;
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>CO.O1CCOCC1>[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of NaOH (1.7 g/12 ml) was added to methyl 4-acetylbenzoate (5.04 g, 28.3 mmol) in MeOH-dioxane (2:1, 60 ml). After stirring at room temperature for 12 hr, the mixture was acidified with 5N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4. Evaporation of solvent gave 4-acetylbenzoic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.CC1C=CC(S(O[CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:7]=[C:2]([O:1][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:3]=[C:4]([CH3:17])[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 77.4 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.26 g, 10.0 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 90° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.68 g, yield 77%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18].CS[C:21](=[N:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[NH:22][C:23]#[N:24].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:18]=[C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21]([NH:22][C:23]#[N:24])=[N:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: NCCCCCCn1c(=O)ccc2ccccc21
Reactant: CSC(=Nc1ccncc1)NC#N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#CNC(=Nc1ccncc1)NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-amino-1-hexyl)-1,2-dihydroquinoline-2-one (320 mg), S-methyl-N-cyano-N′-4-pyridyl-isothiourea (210 mg), triethylamine (0.31 ml), 4-(N,N-dimethylamino)-pyridine (7 mg) and pyridine (10 ml) was stirred overnight at 60° C. After cooling to room temperature the pyridine was removed by evaporation twice with toluene in vacuo and the residue was distributed between water and ethyl acetate. The organic phase was dried and evaporated to yield a crude product which was purified by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (40:10:1.25) as eluent. The pure fractions were pooled, evaporated, triturated with ethyl acetate and dried in vacuo to give the title compound.
Reaction SMILES: CC1(C)CO[C:5]2([CH2:32][CH2:31][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4]C1>O>[CH3:29][N:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C:8]4([CH2:31][CH2:32][C:5](=[O:4])[CH2:6][CH2:7]4)[O:13][C:12]3=[O:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:24][C:25]1=[O:30]
Reactant: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Yield: 48 %

Procedure:
The title compound is prepared from 12,12-dimethyl-3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one following a procedure analogous to that described in Step 10 of Intermediate 2. Yield: 48% of theory; Mass spectrum (ESI+): m/z=395 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.55 (d, J=7.1 Hz, 3H), 1.85-2.05 (m, 5H), 2.08-2.27 (m, 3H), 2.44-2.56 (m, 2H) superimposed by DMSO-d5, 2.81-2.89 (m, 1H), ca. 3.25-3.33 (m, 1H) superimposed by H2O, 3.45 (s, 3H), 5.54 (q, J=7.1 Hz, 1H), 6.57 (dd, J=7.1, 2.0 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 7.42 (dm, J=8.2 Hz, 2H), 7.72 (dm, J=8.2 Hz, 2H), 7.76 (d, J=7.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:27][S:28]([O:11][CH2:10][C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)carbamate (4.8 g, 14.36 mmol) in anhydrous DCM (100 mL) at 0° C. was added triethylamine (4.00 mL, 28.7 mmol) followed by methanesulfonyl chloride (1.343 mL, 17.24 mmol). The reaction was stirred at 0° C. for 1 hr, by which time the LCMS indicated the reaction had gone to completion. The reaction mixture was poured into saturated NaHCO3 solution (100 mL). The mixture was shaken, the layers separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were washed with NaHCO3 solution (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated, giving (S)-2-((tert-butoxycarbonyl)amino)-2-(3-bromo-5-fluorophenyl)ethyl methanesulfonate (5.92 g, 14.36 mmol, 100% yield) as a very pale orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.75 (d, J=8.83 Hz, 1H), 7.43-7.55 (m, 2H), 7.31 (d, J=9.46 Hz, 1H), 4.86-5.00 (m, 1H), 4.30 (dd, J=10.09, 5.04 Hz, 1H), 4.24 (t, J=9.30 Hz, 1H), 3.16-3.23 (m, 3H), 1.36-1.44 (m, 9H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(Nc1ccc(N2CCN(Cc3ccc[nH]3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (310 mg) in 1,2-dichloroethane (20 mL) was added 1H-pyrrole-2-carboxaldehyde (95 mg) and acetic acid (67 mg). The solution was cooled at 0° C. and sodium triacetoxy borohydride (317 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) and the solid obtained was recrystallized from EtOH to give the title compound (180 mg) as white crystals.