Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN1CCN(C)C1=O
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 1,3-dimethyl-2-imidazolidinone (7 g) in benzene (45 ml), phosphorus oxychloride (6 ml) and 4-(2-aminophenyl)morpholine (8.5 g) in benzene (30 ml) was heated for 30 hours at 65°-70° C. The product was recrystallised from hexane to give 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 133°-134° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1

Procedure:
In a manner according to Example 1, ethyl p-aminohydrocinnamate is alkylated with 1-bromohexadecane and potassium carbonate in hexamethylphosphoramide, providing ethyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@H:11]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH3:24][O:23][C:20]1[C:19]([O:25][CH3:26])=[CH:18][C:17]2[C@H:11]3[C@H:10]([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]3)[N:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]=2[CH:21]=1
Reactant: COc1ccc([C@@H]2CN(C)CC[C@@H]2NC(=O)c2ccccc2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccccc1

Procedure:
18 g of cis-4-benzoylamino-3-(3,4-dimethoxyphenyl)-1-methylpiperidine are boiled under reflux in 100 cc of phosphorus oxychloride for 11/2 hours. The reaction mixture is subsequently evaporated to dryness in a vacuum and the resulting oily residue is shaken with methylene chloride and a 2 N caustic soda solution. The organic phase is dried over sodium sulphate and concentrated by evaporation. Crystallization from ethyl acetate yields the title compound as almost colourless crystals having a M.P. of 126°-127°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:39](=[O:41])[CH2:38][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCc1ccc(F)cc1
Product: CN(C(=O)CCc1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-methyl-propionamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-(4-fluorophenyl)propionic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 588.2 [M]+.
Reaction SMILES: ClCl.BrBr.II.[N:7]([P:10](Cl)Cl)([CH3:9])[CH3:8].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[CH3:8][N:7]([P:10]([C:16]1[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=1)[CH3:9]
Reactant: CN(C)P(Cl)Cl
Reactant: Cc1ccc([Mg]Br)cc1
Agent: BrBr
Agent: ClCl
Agent: II
Product: Cc1ccc(P(c2ccc(C)cc2)N(C)C)cc1

Procedure:
U.S. Pat. No. 2,934,564 relates to compounds of the general formula R2PX wherein R represents an alkyl or aryl group and X represents chlorine, bromine or iodine. For example, the reaction of Me2NPCl2 (0.42 mole) with p-tolylmagnesium bromide (0.84 mole) produces dimethylamino-di-p-tolylphosphine. The isolated dimethylamino-di-p-tolylphosphine (31.88 mmoles) was treated with 1428 cc (63.75 mmoles) of anhydrous HCl yielding di-p-tolylchlorophosphine, which was purified by distillation. Similarly, Burg, et al. (J.A.C.S. 80, 1107-09, 1958) disclose the preparation of chlorodimethylphosphine from Me2NPCl2 and suggest the viability of a Grignard route to R2PR'-type phosphines. K. Issleib, et al. (Chem. Berichte 29, 2682-3008, 1959) have shown that Et2NPCl2 (Et=ethyl) and cyclohexylmagnesium chloride react in a 1:1.25 molar ratio to form diethylaminocyclohexylchlorophosphine in 57.5% yield. The authors suggest this reaction can be exploited to prepare unsymmetrical chlorophosphines of the type RR'PCl, but no mention is made of the possibility of further reaction to unsymmetrical tertiary phosphines of the type RR'R"P.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22](N)[C:21]=4[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:16][CH2:15]3)[N:11](C)[CH:12]=2)=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].BrC1C(N2CCC(C3NC=C(C4C=CC=C(C(F)(F)F)C=4)N=3)CC2)=NC=NC=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([C:10]4[NH:11][CH:12]=[C:8]([C:5]5[CH:6]=[CH:7][CH:2]=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=5)[N:9]=4)[CH2:19][CH2:18]3)=[N:25][CH:24]=[N:23][CH:22]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1
Agent: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ncncc4Br)CC3)n2)c1
Product: COc1ccc(-c2cncnc2N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamine using 5-Bromo-4-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine instead of 5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine. LC-MS: (M+1=480, obsd.=480).
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.Cl.[Br:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)N)=[CH:15][CH:14]=1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[C:20]3[C:21](=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:3]([C:4]3([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]3)=[C:2]2[CH3:10])=[CH:15][CH:14]=1
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Reactant: CC(=O)CC1(CC#N)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C1(CC#N)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a 0° C. mixture of the ketone from Step 4 (920 mg, 6.71 mmol) and the hydrazine from Step 5 (2.15 g, 7.0 mmol) in 35 mL toluene was added acetic acid (0.97 mL, 17 mmol). The mixture was warmed to room temperature and stirred 1 h, then concentrated to dryness. The residue was dissolved in toluene and heptane and concentrated again and the process repeated until there was no more acetic acid remaining. The residue was then dissolved in 30 mL dioxane and treated with HCl (4M solution in dioxane, 4 mL, 16 mmol). The mixture was heated to 60° C. for 1.5 h, then cooled and partitioned between water and ethyl acetate. The organic phase was washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated. Purification by flash chromatography (15% ethyl acetate/hexanes) provided 2.32 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([F:20])[CH:13]=[C:14]([F:19])[CH:15]=2)[CH2:10]1)[CH2:5][CH2:6][CH3:7].[Li+].[OH-]>C1COCC1.O>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:20])[CH:13]=1)[CH2:10][CH:9]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:21])=[O:2])[CH2:18][CH2:17]2
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid methyl ester (1 equiv) is dissolved in THF:water (5:1) and LiOH (1.2 equiv) is added. The reaction is stirred overnight at rt, the solvent is removed, water added, and the pH is adjusted to 7 using 1N hydrochloric acid. The solid is filtered, washed with water and diethyl ether, and dried to afford 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid; Acid derived from diasteromer 1: H1 NMR (400 MHz, CD3OD) 0.99 (t, 3H, J=7.5), 1.48 (m, 2H), 1.82 (m, 3H), 2.36 (m, 1H), 2.65 (m, 1H), 2.95 (m, 2H), 3.28 (s, 1H), 3.42 (m, 1H), 3.74 (m, 1H), 6.80 (m, 2H); (MS m/z 284.3 (M+1). Acid derived from diasteromer 2: H1 NMR (400 MHz, CD3OD) 0.94 (t, 3H, J=7.6), 1.42 (m, 2H), 1.56 (m, 3H), 1.96 (m, 1H), 2.25 (m, 1H), 2.85 (m, 3H), 3.15 (m, 1H), 3.25 (m, 1H), 6.64 (m, 2H); MS m/z 284.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH2:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=4)[CH2:18][CH2:17]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of trans-2-(4-cyclopropylphenyl)cyclopropanamine (90 mg, 0.519 mmol) in methanol (2 mL) were added methyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (156 mg, 0.597 mmol) and acetic acid (8.92 μL, 0.156 mmol), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52.2 mg, 0.831 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with 10% NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using reverse-phase HPLC to give 120 mg of product as off-white solid. MS: (M+H)+=419.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.56-0.71 (m, 2H), 0.89-1.07 (m, 2H), 1.32-1.43 (m, 1H), 1.51-1.77 (m, 3H), 1.83-1.94 (m, 1H), 1.97-2.25 (m, 3H), 2.53 (ddd, J=10.11, 6.44, 3.41 Hz, 1H), 2.93-3.25 (m, 5H), 3.49-3.64 (m, 2H), 3.86-4.00 (m, 3H), 4.43 (s, 2H), 6.97-7.17 (m, 4H), 7.72 (d, J=8.08 Hz, 2H), 8.14 (d, J=8.08 Hz, 2H).
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([O:53]C)=O)=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.CN>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([NH:2][CH3:1])=[O:53])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CN
Product: CNC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and methylamine. m/e+ 368 for C18H15F2N6O (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:16]([NH2:18])=[O:17])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1.CS(O[CH:24]1[CH2:30][CH:29]2[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[C:16]([C:13]1[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[N:12][C:3]([S:2][CH3:1])=[N:4][C:5]=3[C:6]=2[N:15]([CH:24]2[CH2:30][CH:29]3[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:38])([Cl:39])[Cl:37])=[O:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)[N:14]=1)(=[O:17])[NH2:18]
Reactant: CS(=O)(=O)OC1CC2CCC(C1)N2C(=O)OCC(Cl)(Cl)Cl
Reactant: CSc1ncc2ccc3c(C(N)=O)n[nH]c3c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ncc2ccc3c(C(N)=O)nn(C4CC5CCC(C4)N5C(=O)OCC(Cl)(Cl)Cl)c3c2n1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
8-(Methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 50 mg (0.193 mmol) in DMF (8 ml), were reacted with 2,2,2-trichloroethyl 3-[(methylsulfonyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 200 mg (0.52 mmol) and cesium carbonate 140 mg (0.43 mmol) at 90° C. for 4 hours. The mixture was cooled at r.t. and portioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The crude was purified by column chromatography eluting with DCM/EtOH 9/1 to provide 2,2,2-trichloroethyl 3-[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate as a off-white solid 73 mg (70%). The compound (134 mmol) was dissolved in THF (5 ml), acetic acid (5 ml) and zinc dust 35 mg (0.536 mmol) were added. The mixture was heated up to 50° C. and stirred 18 hours. The volatiles were removed in vacuum and the residue was purified by chromatography eluting with DCM/MeOH 95/5. A further purification was required and was performed by prep-HPLC method 1, to obtain the title compound 25 mg (50%). LC/MS (254 nm) HPLC method 2 Rt 4.08 min. 1H NMR (401 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.25 (d, J=8.67 Hz, 1H), 7.62-7.79 (m, 3H), 7.52-7.60 (m, 1H), 6.21-6.54 (m, OH), 3.68 (br. s., 2H), 2.76 (s, 2H), 2.22-2.36 (m, 2H), 2.02 (br. s., 2H), 1.78-1.98 (m, 5H). HRMS (ESI) calcd for C18H20N6OS [M+H]+ 369.1492 found 369.15.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)=[CH:7][C:6]=1[N:22]1[CH:26]=[N:25][N:24]=[N:23]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)=[CH:7][C:6]=1[N:22]1[CH:26]=[N:25][N:24]=[N:23]1
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)O)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(OCC(C)(C)O)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A reaction mixture solution prepared by dissolving 9.9 mg of ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.2 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic phase was concentrated and purified by a conventional method to obtain 4.8 mg of 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][CH2:12]C)(=[O:10])[CH3:9]>>[C:1]1([CH3:7])[CH:6]=[CH:5][C:4]([CH2:9][C:8]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Product: COC(=O)Cc1ccc(C)cc1

Procedure:
Rf=0.81 (toluene:ethyl acetate=2:1)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[I:19]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([I:19])[C:7]([F:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(C2CC2)cn1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ncc(C2CC2)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Cool a solution of 5-cyclopropyl-2-fluoro-pyridine (1.3 g, 9.5 mmol) in THF (20 mL) to −75° C. in a dry ice-acetone bath under nitrogen. Add lithium diisopropylamide (2 M in THF, 6 mL, 12 mmol) during a period of 30 min. Stir the mixture for another 3 h before adding iodine (2.9 g, 11.4 mmol, dissolved in 50 mL of THF). Keep stirring for 2 more hours before adding water (100 mL) to the mixture. Then allow to warm to RT during 1 h under stirring. Treat the mixture with a saturated sodium thiosulfate solution (50 mL). Extract the solution with ether. Concentrate the solution in vacuo. Purify by column chromatography (hexane→20% ethyl acetate in hexane) to afford the title compound as a yellow oil (1.7 g, 68%). 1H NMR (400 MHz-CDCl3) δ 7.99 (d, J=3 Hz, 1H), 7.39 (td, J=3, 5 Hz, 1H), 6.79 (dd, J=3, 8 Hz, 1H), 0.96-1.02 (m, 2H), 0.63-0.69 (m, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].Cl.NCC(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:42])[NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(N)(CO)CO
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[CH2:21][CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:19][CH2:18]1)[CH2:21][CH2:22][CH3:23]
Reactant: c1ccc(N2CCNCC2)c(C2CCCCCC2)c1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2ccccc2C2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a mixture of the 1-(2-cycloheptylphenyl)piperazine (25 mg, 0.0967 mmol) produced in Example (44c) and tetrahydrofuran (1 mL) were added butyraldehyde (0.011 mL, 0.126 mmol), sodium triacetoxyborohydride (26.6 mg, 0.126 mmol) and acetic acid (0.011 mL, 0.183 mmol), and the mixture was stirred for 19 hours and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 26.7 mg of 1-butyl-4-(2-cycloheptylphenyl)piperazine as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14]Cl)[CH:13]=1>>[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:11]=[N:10][CH:9]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=C1CCCN1
Product: O=C1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], pyrrolidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a white solid. MS: 251.1, 257.1 (M+H+).
Reaction SMILES: [ClH:1].CC(C)(C)C(O[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[S:10][CH2:9]1)=O>O1CCOCC1>[ClH:1].[NH2:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[S:10][CH2:9]1
Reactant: CC(C)(C)C(=O)ON[C@H]1CSc2c(cccc2-c2ccccc2)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CSc2c(cccc2-c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8 mL of a solution of hydrogen chloride in dioxane (4 M) are placed in a 50 mL round-bottomed flask containing 410 mg of 40 (1.107 mmol). The mixture is stirred for 4 hours at room temperature under argon. A white precipitate forms, which is filtered off by suction and washed with 3 mL of dioxane and then 5 mL of isopropyl ether. 260 mg of amine 41 (white solid) are thus obtained in the form of the hydrochloride.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-ol (prepared according to the procedure of Kayser, Margaret M.; Clouthier, Christopher M. Journal of Organic Chemistry (2006), 71(22), 8424-8430, 11 g, 70 mmol) in DCM (100 mL) was treated with TEA (11 mL, 77 mmol) followed by TsCl (Aldrich, 13.3 g, 70 mmol) slowly at 0° C. The reaction was warmed to room temperature over 2 hours. The solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give white solid, which was then purified by silica gel column on a CombiFlash® system (Teledyne Isco, Inc, Lincoln, Neb.) system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as white solid.