Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1cnn2CC1CCCNC1
Reaction time: 2 h
Yield: 126.9 %

Procedure:
A solution of tert-butyl 3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.118 g, 0.327 mmol) in DCM (1.6 mL) was treated with trifluoroacetic acid (0.4 mL) at ambient temperature and stirring continued for 2 hours. The solvent was concentrated and the resulting gum was dried under high vacuum to afford 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.108 g, 92% yield) as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([C:27]2[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].O1CCC(C(NN)=O)[CH2:37]1.COCCC(NN)=O>>[CH2:1]([C:3]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([C:27]2[NH:31][C:30]([CH:32]3[CH2:37][CH2:35][O:34][CH2:33]3)=[N:29][N:28]=2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2]
Reactant: NNC(=O)C1CCOC1
Reactant: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: COCCC(=O)NN
Product: CCc1cc(CC)c(-c2nnc(C3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 209) but using tetrahydrofuran-3-carbohydrazide (compound 38.2) instead of 3-methoxypropanehydrazide (compound 143.1). m/z (ES+) 484.05 (M+H)+.
Reaction SMILES: NC1C=CC=CC=1.[CH3:8][N:9]([CH3:36])[C:10]([N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[NH:35][C:21]3[N:22]=[CH:23][N:24]=[C:25]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([NH2:33])[C:27]=4[CH3:34])[C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)=[O:11].CCN(C(C)C)C(C)C.[CH3:46][N:47]([CH3:57])[C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:36][N:9]([CH3:8])[C:10]([N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[NH:35][C:21]3[N:22]=[CH:23][N:24]=[C:25]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([NH:33][C:52](=[O:53])[C:51]5[CH:50]=[CH:49][C:48]([N:47]([CH3:46])[CH3:57])=[CH:56][CH:55]=5)[C:27]=4[CH3:34])[C:20]=3[CH:19]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(N(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of aniline Intermediate 6 (84 mg, 0.213 mmol) in DCM/pyridine (2:1, 30 ml) were added DIPEA (0.372 ml, 2.13 mmol), 4-dimethylaminobenzoyl chloride (43 mg, 0.234 mmol), and DMAP (2.6 mg, 0.021 mmol). The resulting mixture was stirred at room temperature for 75 hrs. The solvents were removed in vacuo and the resulting mixture was purified by reversed phase HPLC (MeCN/H2O) to afford Example 15.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[C:14]([C:17]([NH:19][NH2:20])=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.[C:21](=S)=[S:22].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C.O1CCCC1>[S:8]1[C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:21]([SH:22])=[N:20][N:19]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc2ncsc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: Sc1nnc(-c2ccc3ncsc3c2)o1
Yield: 82.6 %

Procedure:
A suspension of benzothiazole-6-carbohydrazide trifluoroacetate (4.92 g, 16.0 mmol), carbon disulfide (2.41 mL, 40.0 mmol) and triethylamine (5.58 mL, 40.0 mmol) in ethanol (60 mL) was heated under reflux for 1.5 hr. After cooling, the reaction mixture was diluted with ethyl acetate/tetrahydrofuran, washed with 1M hydrochloric acid and water, and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran to give the title compound (3.11 g, yield 83%) as pale-yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CC(C)=O>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[CH:25]=[CH2:24]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(C)(C)c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of bisphenol A (sigma-Aldrich), 36.35 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and the homogeneous mixture thus obtained was refluxed. During the refluxing, 8.33 ml of allyl bromide (Sigma-Aldrich) was added in a dropwise manner and allowed to react overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. The solvent was evaporated to obtain a coarse product. A target product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 4-(2-(4-(allyloxy)phenyl)propane-2-yl)phenol. The reaction scheme of the 1st step and the NMR data of the intermediate product (11) thus obtained are as follows.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([C:28]([O:30][CH3:31])=[O:29])[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:22](Cl)=[O:23])[C@@H:10]([CH:25]2[CH2:27][CH2:26]2)[CH2:9]1.[F:41][C:42]([F:46])([F:45])[CH2:43][OH:44]>>[F:41][C:42]([F:46])([F:45])[CH2:43][O:44][C:22]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:40])([F:39])[F:1])[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:9][C@@H:10]1[CH:25]1[CH2:26][CH2:27]1)=[O:23]
Reactant: OCC(F)(F)F
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2ccc(C(F)(F)F)cc21
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OCC(F)(F)F)c2ccc(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl chloride (Example 102B) (20 mg) in 2,2,2-trifluoroethanol (5 mL) was heated to reflux. After 1 h, the reaction was cooled and concentrated, and the residue was chromatographed (5-10% EtOAc/hexane) to afford the title product (22 mg, 77%). MS m/z 685 (M++19); 1H NMR (CDCl3) δ 3.82 (s, 3H), 7.17 (C5, s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[OH-].[Na+].Br[C@H:11]([CH3:15])[C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:4]1[N:3]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:2]=[N:1][CH:6]=[CH:5]1
Reactant: C[C@@H](Br)C(=O)O
Reactant: O=c1ccnc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1cnccc1=O
Temperature: 85 °C

Procedure:
To pyrimidin-4(3H)-one (0.908 g, 9.45 mmol) was added a 5 N sodium hydroxide solution (3.8 ml) followed by (2R)-2-bromopropanoic acid (0.95 ml, 11 mmol). The reaction mixture was heated at 85° C. for 1 h. After cooling to ambient temperature the reaction was neutralized with 2 N hydrochloric acid (5.2 ml) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in aeetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. 1H NMR (DMSO-d6) δ: 8.48 (d, J=2.7 Hz, 1H), 7.88 (dd, J=7.8, 2.8 Hz, 1H), 6.12 (d, J=7.6 Hz, 1H), 5.04 (q, J=7.3 Hz, 1H), 1.64 (d, J=7.5 Hz, 3H). LC/MS 169.1 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].CC(N(C)C)=O>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(NCCNC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(C(=O)NCCNC(=O)c2ccc(N)cc2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
In a 2 litre volume autoclave for high pressure, N,N'-bis(p-nitrobenzoyl)ethylenediamine (140 g; 0.39 mol), Raney nickel (5 g) and dimethylacetamide (700 ml) are charged, and the atmosphere in the reaction vessel is well replaced by hydrogen. Then, the contents are stirred at 70 to 100° C for about 3 hours while introducing hydrogen (90 kg/cm2) to effect hydrogenation of the nitro group. The reaction mixture is heated to dissolve the produced diamine, Raney nickel is removed off by filtration, and the filtrate is poured into water (5 liters). The resultant precipitate of the diamine is separated and dried to obtain crude crystals (108 g; yield, 93%). Recrystallization from dimethylacetamide (1.5 liters) affords white crystals melting at 293.5° to 295° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[C:18]4[CH3:24])[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1.[CH:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:25][C:4]1[CH:3]=[C:2]([NH:1][CH2:26][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[CH3:24])[CH:9]=1
Reactant: Cc1cc(N)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-amino-2-methylphenyl)-4-(3-methyl-1H-indazol-5-yl)pyrimidin-2(1H)-one (25 mg, 0.06 mmol) in 6 mL dichloroethane were added tert-butyl 4-formylpiperidine-1-carboxylate (76.6 g, 0.36 mmol), NaBH(OAc)3 (76 mg, 0.36 mmol), and 500 μL acetic acid. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous NaHCO3 (15 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl 4-((3-methyl-4-(6-(3-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenylamino)methyl)piperidine-1-carboxylate, which was submitted to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+]>CN(C)C=O.CO.[Cu]Br>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu]Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cnc2[nH]ccc2c1

Procedure:
Under an argon atmosphere and in an anhydrous medium, 1 g (5.07 mmol) of the compound obtained in Step C is dissolved in a mixture of 25 ml of N,N-dimethylformamide and 22 ml of methanol; 6.86 g (126.75 mmol) of sodium methanolate and 1.43 g (10.30 mmol) of copper(I)bromide are added at room temperature. The mixture is heated at reflux for 3 hours. After removal of the solvents by evaporation, the residue is taken up in water and ethyl acetate and then filtered over Celite. The organic phase is washed with water, dried over magnesium sulphate and evaporated to yield a solid, which is purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 7:3). The title compound is obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][O:12][CH3:13])=[C:7]([CH:9]=1)[NH2:8].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:22]([O:21][C:19]([C:18]1[C:17](=[O:16])[C:9]2[C:7](=[C:6]([O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[NH:8][CH:24]=1)=[O:20])[CH3:23]
Reactant: COCOc1ccc(OC)cc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(OCOC)ccc(OC)c2c1=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
5-Methoxy-2-methoxymethoxyaniline (3.6 g) and diethyl ethoxymethylenemalonate (4.5 g) were heated at a temperature of 100°-120° C. for 1 hour. Eighty milliliter of diphenyl ether was added to the mixture, and the resulting mixture was further heated at 250°-260° C. for 1.5 hours. After the mixture was left to cool down to room temperature, it was purified by silica gel column chromatography (Wako Gel C-200, 140 g). Elution with a mixed solvent of chloroform (97 parts) and methanol (3 parts) gave 3.0 g of 3-ethoxycarbonyl-5-methoxy-8-methoxymethoxy-4(1H)-quinolone (compound 5).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:10]N1C(=O)CCC1=O>C(#N)C>[Cl:10][C:3]1[C:2]([OH:1])=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1
Reactant: N#Cc1cncc(O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: N#Cc1cnc(Cl)c(O)c1
Temperature: 107 °C
Yield: 21.4 %

Procedure:
A mixture of 5-hydroxy-nicotinonitrile (2.0 g, 16.66 mmol), and N-chlorosuccinimide (3.3 g, 25.0 mmol) in acetonitrile (33 mL) was heated in a sealed tube at 107° C. overnight. Acetonitrile was removed under reduced pressure, the residue was diluted with EtOAc (100 mL). The organic layer was washed with water (10 mL) and brine (2×10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by flash chromatography on silica gel using 20-80% EtOAc/hexanes gradient elution to yield the title compound (0.55 g, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H); MS (ES) m/z: 153 (M−1)−.
Reaction SMILES: [OH:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30]>C1C=CC=CC=1>[OH:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]=1[O:1][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CO
Reactant: CC(C)[Si](OCCc1cccc(CC2=C(O)CCC2=O)c1)(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CC(C)COC1=C(Cc2cccc(CCO)c2)C(=O)CC1
Yield: 81 %

Procedure:
A mixture containing 46 (0.294 g, 0.757 mmol), paratoluensolfonic acid (0.005 g), i-butanol (1.0 mL) and benzene (4.0 mL) was heated to reflux for 12 h. The reaction mixture was then concentrated and the residue so obtained was purified by silica gel column chromatography using 5% of methanol in dichloromethane as eluent, obtaining the desired compound. Yield: 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: COC(CN)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CNCc1ccc(F)cc1Cl)OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-fluorobenzaldehyde (3.17 g, 20 mmol, 1.0 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1.0 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 2.5 hours. The mixture was concentrated in vacuo and dried under h.v. The residue was dissolved in EtOH (100 mL). The solution was cooled to 0° C. and NaBH4 (1.14 g, 30 mmol, 1.5 eq.) was added portionwise. The cooling bath was removed and the solution was stirred at r.t. for 18 hours. The resulting reaction mixture was quenched with sat. aq. NaHCO3 soln. (150 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (2-chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine as a yellow oil. The product was used without further purification.
Reaction SMILES: [OH-].[Li+].[O:3]=[S:4]1(=[O:41])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]([O:20]CC)=[O:19])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7][C:6]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:35][CH3:36])[CH2:5]1>C1COCC1.O>[O:41]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]([OH:20])=[O:19])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7][C:6]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:35][CH3:36])[CH2:5]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C(=O)OCC)c3ccccc3)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C(=O)O)c3ccccc3)cc2S(=O)(=O)C1
Yield: 92.3 %

Procedure:
Lithium hydroxide (0.019 g) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-phenyl-1′-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 3; 0.244 g, 0.397 mmol) in THF/H2O (2/1, 3 ml). After 2 days the solvent was removed under reduced pressure and the crude mixture was purified by HPLC to give the title compound 0.215 g (92%) as a white solid. NMR (CD3OD) 0.60–0.80 (m, 6H), 0.90–1.25 (m, 4H), 1.30–1.60 (m, 4H), 3.05–3.30 (m, 2H), 3.40–3.90 (m, 2H), 5.55 (s, 1H), 6.85–7.70 (m, 12H).
Reaction SMILES: Br[C:2](=[CH:4][CH3:5])[CH3:3].[Li].C(O[C:10](=[O:16])[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])C.O>C(OCC)C>[OH:16][C:10]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])([C:2]([CH3:3])=[CH:4][CH3:5])[C:4]([CH3:5])=[CH:2][CH3:3]
Reactant: CC=C(C)Br
Reactant: CCOC(=O)CCN(C)C
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CC=C(C)C(O)(CCN(C)C)C(C)=CC

Procedure:
2-bromo-2-butene (108 g; 0.800 mol) was added to 10.0 g of lithium (1.43 mol) in diethyl ether (300 ml) in about 30 minutes with reflux. After stirring overnight (17 hours), ethyl-3-(N,N-dimethylamino)propionate (52.0 g; 0.359 mol) was added to the reaction mixture in about 15 minutes. After stirring for 30 minutes at room temperature 200 ml of water was added dropwise. After separation the water phase was extracted two times with 50 ml of CH2Cl2. The organic phase was reduced by evaporation and the residue was distilled at reduced pressure. The yield was 51.0 g (67%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH2:11]([O:18][C:19]([C:21]1([C:52]([OH:54])=O)[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:41]([F:51])[CH:40]=4)[O:36][N:35]=3)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[CH2:11]([O:18][C:19]([C:21]1([C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[O:54])[CH2:22][CH2:23][N:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:41]([F:51])[CH:40]=4)[O:36][N:35]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)C1(C(=O)N2CCOCC2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Hydroxybenzotriazole (0.183 g, 0.0012 mol) is added to a stirred solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (0.6 g, 0.0010 mol) in tetrahydrofuran (20 mL). Reaction mixture is stirred for 30 minutes at room temperature. Morpholine (0.13 mL, 0.0015 mol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.288 g, 0.0015 mol) are added to the reaction mixture and stirred for over night at room temperature. Demineralized water (10 mL) is added to the reaction mixture, tetrahydrofuran layer is separated and the aqueous layer is extracted with ethyl acetate (2×15 mL). Combined organic layer is dried over sodium sulphate and concentrated under reduced pressure to yield a crude viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate) to get 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(morpholine-4-carbonyl)-piperidine-4-carboxylic acid benzyl ester.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[Cl:21][C:22]1[CH:44]=[C:43]([F:45])[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[CH:41][C:23]=1[C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([C:38]([OH:40])=O)[CH:28]=1)=[O:25].C(N(CC)C(C)C)(C)C.[CH2:61]([CH2:63][NH2:64])[OH:62]>CN(C=O)C>[Cl:21][C:22]1[CH:44]=[C:43]([F:45])[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[CH:41][C:23]=1[C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([C:38]([NH:64][CH2:63][CH2:61][OH:62])=[O:40])[CH:28]=1)=[O:25]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Reactant: NCCO
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
TPTU (510 mg, 1.72 mmol) and 5-(2-chloro-4-fluoro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 108, 500 mg, 1.14 mmol) were dissolved in DMF (2.5 mL) at 0° C. N,N-diisopropylethylamine (0.6 mL, 3.43 mmol) was then added and the mixture stirred at 0° C. for 15 minutes. Ethanolamine (99.5 mL, 1.65 mmol) was then added and the mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the resulting brown solid triturated with dichloromethane/TBME/heptane (4:2:0.5, 5 mL) to give a white solid, which was further triturated with MeOH (5 mL) to afford the title compound as a white solid (262 mg, 48%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]([F:16])([F:15])[CH2:9]OCC(O)=O>ClCCl.CN(C)C=O>[F:7][C:8]([F:16])([F:15])[CH2:9][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: O=C(O)COCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCC(F)(F)F

Procedure:
A solution of oxalyl chloride (20 mL, 0.23 mol, 1.15 eq) in dry dichloromethane (50 mL) was added dropwise at room temperature, with stirring, to a solution of (2,2,2-trifluoroethoxy)ethanoic acid (int. Patent Appl., Publication No. WO 87/07270, 31.6 g, 0.2 mol) and N,N-dimethylformamide (5 drops) in dry dichloromethane (400 mL). The mixture was stirred for an additional hour, then heated under reflux for 2 hours, cooled and the bulk of the solvent removed by distillation (bp 40-45° C./760 mm Hg). The residue was transferred to a Claisen distillation flask and the remaining solvent and oxalyl chloride removed by distillation (bp 45-60° C./760 mm Hg). Vacuum distillation of the residue then afforded the product, bp 50-55°/25-32 mm Hg. δH (CDCl3) 4.00 (2H, q, 3JHF 8.3) and 4.57 (2H, s).