Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[I:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=O.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.C1COCC1.O>[I:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][NH:16][CH3:17]
Reactant: CNC(=O)c1ccccc1I
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CNCc1ccccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Lithium aluminum hydride (14.8 g, 390 mmol) is suspended in dry diethyl ether (250 mL) and cooled to 0° C. Aluminum chloride (16.0 g, 121 mmol) dissolved in dry diethyl ether (250 mL) is added dropwise at 0-5° C. The cooling bath is removed and the mixture is stirred at ambient temperature for 1 hour. The resulting aluminum hydride reagent solution is cooled to 0° C. followed by dropwise addition of 2-iodo-N-methyl-benzamide (50.8 g, 195 mmol) dissolved in dry THF (500 mL). After complete addition the solution is allowed to heat to ambient temperature and stirring is continued for 16 hours. The mixture is cooled to 10° C. followed by slow dropwise addition of water (30 mL) followed by 2M sodium hydroxide (30 mL) and water (150 mL). MgSO4 is added and the mixture is stirred for 10 minutes, filtered and concentrated in vacuo. The remanence is redissolved in ethyl acetate (500 mL), dried (MgSO4) and concentrated again to furnish 45.2 g (94%) of (2-iodo-benzyl)-methyl-amine as an oil. (2-Iodo-benzyl)-methyl-amine (20.0 g, 80.9 mmol) is dissolved in dry THF (300 mL) and di-tert-butyl dicarbonate (18.5 g, 85.0 mmol) is added. The mixture is stirred for 1 hour at ambient temperature. The volatiles are removed by means of evaporation and the crude mixture is purified by silica gel chromatography eluting with ethyl acetate-heptane (1:4) to furnish 28.5 g (quant.) of the title compound as an oil.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23](/[CH:29]=[CH:30]\[CH3:31])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.IC>C1COCC1>[CH3:1][C@@H:24]([C@H:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1)/[CH:29]=[CH:30]\[CH3:31])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)[N-]C(C)C
Reactant: C/C=C\[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C/C=C\[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H](C)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide (0.2 mL, 2 mmol in heptane/THF/ethylbenzene) in THF (1.0 mL) was slowly added (S,Z)-methyl 3-(4-(benzyloxy)phenyl)hex-4-enoate 41.1 (0.50 g, 2 mmol) in THF (5.0 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and then iodomethane (0.1 mL, 2 mmol) was added. The reaction mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was purified by silica gel, eluent with hexane/EtOAc 95/5 to 10/90 to give the title compound as a major product 41.2 in a ratio of 95:5. 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (d, J=7.04 Hz, 3H) 1.46-1.61 (m, 1H) 2.64 (m, 1H) 3.34 (s, 3H) 4.90 (s, 2H) 5.35-5.53 (m, 2H) 6.76-6.84 (m, 2H) 6.97-7.07 (m, 2H) 7.15-7.34 (m, 5H). MS ESI (pos.) m/e: 325.1 (M+H)+. It is possible that the stereochemistry at the carbon atom adjacent to the carbonyl is opposite that shown which would carry through to the final product of this Example. However, it is believed that the structure of 41.2 is as shown above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[N:20]1[NH:21][N:22]=[N:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:20]=[N:21][NH:22][N:23]=2)=[CH:30][CH:29]=1)=[O:9]
Reactant: NCc1ccc(-c2nn[nH]n2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Agent: Cl
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(Cl)ccc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 75 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2 of Example 67) and 1-[4-(2H-tetrazol-5-yl)phenyl]methanamine hydrochloride: 1H-NMR (DMSO-d6) δ 9.01 (1H, t, J=6.0 Hz), 7.93 (2H, d, J=8.2 Hz), 7.70 (1H, d, J=2.6 Hz), 7.53–7.46 (3H, m), 7.29–7.10 (4H, m), 6.93 (1H, d, J=8.9 Hz), 4.52 (2H, d, J=6.1 Hz); MS (ESI) m/z 424 (M+H)+, 422 (M−H)−.
Reaction SMILES: [Si]([O:18][CH:19]([CH2:41][O:42][P:43]([OH:46])([OH:45])=[O:44])[CH2:20][O:21][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+]>ClCCl>[OH:18][CH:19]([CH2:41][O:42][P:43]([OH:45])([OH:46])=[O:44])[CH2:20][O:21][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COP(=O)(O)O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COP(=O)(O)O
Yield: 78 %

Procedure:
6 (1 mmol) is dissolved in 10 ml of dichloromethane, and 25 ml of a 1% methanolic NaOH solution is added. This is concentrated after 20 hours at room temperature, and the residue is acidified with 1N HCl. The mixture is extracted with ethyl acetate. The combined organic phases are washed with 20 ml of H2O and dried over MgSO4, filtrated and concentrated. The residue is treated with methanol. Yield: 78% of colorless crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:33]([CH3:34])=[CH:32][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23](=[O:29])[C:22]4([CH3:31])[CH3:30])[S:18][C:14]=2[C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:33]([CH3:34])=[CH:32][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23](=[O:29])[C:22]4([CH3:30])[CH3:31])[S:18][C:14]=2[C:13]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)C(C)(C)C(=O)N4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(c3)C(C)(C)C(=O)N4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
The crude (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)benzo[d]thiazol-6-yl)acetate from the reaction above was treated with 1.0 M aq NaOH (2 mL), THF (4 mL), and absolute EtOH (2 mL). The reaction was heated to 50° C. for 19 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C31H31ClN2O4S: 563.2, 565.2 (M+H+); Found: 563.3, 565.3 (M+H+). +). 1H NMR (400 MHz, CD3OD): δ 8.05-7.94 (m, 2H), 7.81 (s, 1H), 7.73-7.64 (m, 1H), 7.64-7.54 (m, 3H), 7.14 (d, J=8.2 Hz, 1H), 5.26 (s, 1H), 3.27 (s, 3H), 2.61 (s, 3H), 1.41 (s, 6H), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:9]1[CH2:10][CH2:11][C@@H:7]([F:6])[CH2:8]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: F[C@@H]1CCNC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 357.5 %

Procedure:
Chloroacetyl chloride (632 μL, 7.94 mmol) was added dropwise to a solution of (3R)-3-fluoropyrrolidine (1 g, 7.94 mmol) and triethylamine (2.2 mL, 15.9 mmol) in CH2Cl2 (20 mL) at 5° C. The reaction mixture was stirred at room temperature for 1 h. Water and CH2Cl2 were added. The layers were separated and the aqueous was extracted with CH2Cl2. The combined organics were dried (MgSO4), filtered and concentrated in vacuo, to yield 2-chloro-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (4.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:25]3[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CCN1CCC(=O)CC1
Product: CCN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 50 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-ethyl-4-piperidone using standard reductive amination conditions. The resulting crude solid was triturated with a small amount of diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-ethyl-piperidin-4-yl)-methyl-amine as a solid (50% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 347 as a solid (75% yield). NMR (CDCl3, 400 MHz), 1.10 (3H, t, J=7.2), 1.56-1.73 (2H, m), 1.84-1.95 (4H, m), 2.38 (3H, s), 2.42 (2H, q, J=7.0), 2.51-2.58 (1H, m), 3.06 (2H, d, J=11.8), 3.88-3.91 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=469
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=O)[CH2:16]2)[O:14][CH2:13][CH2:12]1>>[O:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[CH2:16]2)[O:14][CH2:13][CH2:12]1
Reactant: O=C(C1CCCC2(C1)OCCO2)N1CCN(c2ccccn2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: c1ccc(N2CCN(CC3CCCC4(C3)OCCO4)CC2)nc1
Yield: 92.6 %

Procedure:
From aluminum chloride (5.39 g), lithium aluminum hydride (4.61 g) and 1-(1,4-dioxaspiro[4.5]dec-7-ylcarbonyl)-4-(2-pyridinyl)piperazine (40.22 g) (Step A) using the procedure of Example A, Step C is obtained 35.66 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:30]1(/[CH:36]=[CH:37]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>COC>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:37]=[CH:36]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(Cl)n2)sc1C(=O)NCc1ccccc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2cncc(/C=C/c3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a solution of 2-(6-chloro-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (40 mg, 0.12 mmol, 1.0 equiv) in dimethyl ether (0.6 mL) was added Na2CO3 (25 mg, 0.23 mmol, 2.0 equiv), trans-2-phenylvinyl boronic acid (43 mg, 0.29 mmol, 2.5 equiv), CombiPhos Pd-6 (6.0 mg, 0.01 mmol, 0.1 equiv) and water (0.2 mL) in a sealed tube. The reaction was heated in the microwave oven at 100° C. for 25 min. After cooling, the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 5:95, v/v] to give 4-methyl-2-[6-((E)-styryl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (32 mg, 67%). 1H NMR (400 MHz, CD2Cl2) δ 9.17 (s, 1H), 8.64 (s, 1H), 7.83 (d, J=16.0 Hz, 1H), 7.62-7.64 (m, 2H), 7.28-7.43 (m, 8H), 7.19 (d, J=16.0 Hz, 1H), 6.25 (bs, 1H), 4.61 (d, J=1.0 Hz, 2H), 2.74 (s, 3H); HRMS (M+H)+=413.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)ccc1F
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (30.0 g, 148 mmol) in EtOH was added sodium borohydride (8.39 g, 222 mmol) at 0° C. The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0° C., and quenched with aq. saturated NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo to yield the titled compound (30.3 g, quantitative) as a white sold, which was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:23])[C:19]=2[C:20]([OH:22])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:23])[C:19]=3[C:20](=[O:22])[C:12]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(Nc2ccc(Cc3ccccc3)cc2)c1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4)cc3c(=O)c21
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A mixture of 4-[(4-benzylphenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 11, step 1, 4.86 g, 15.81 mmol) in phosphorus oxychloride (40 ml) was refluxed for 3 h. After cooling to room temperature, the mixture was concentrated and dried in vacuo. The mixture was dissolved in ethyl acetate (300 ml), washed with water (100 ml) and saturated aqueous sodium bicarbonate (100 ml×2) and dried over magnesium sulfate. Removal of solvent gave the dark red residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1/3) to afford 3.86 g (79%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.C(O)=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:31])[CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: O=CO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: O=C(CCN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 20 g (50 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne, 1.0 g (3 mmole) of mercuric sulfate and 55 ml of formic acid in 50 ml of methylene chloride was stirred at room temperature for 30 min. The mixture was poured over ice and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ethyl acetate and ether to give a colorless solid. Recrystallization from acetone gave colorless prisms, mp 163°-164° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]3[N:25]=[CH:24][CH:23]=[CH:22][C:16]=3[C:17]([O:19]CC)=[O:18])[S:13][CH:14]=2)=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]3[N:25]=[CH:24][CH:23]=[CH:22][C:16]=3[C:17]([OH:19])=[O:18])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cccnc1-c1nc(-c2ccc(F)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccnc1-c1nc(-c2ccc(F)cc2)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
3 ml of a 2N NaOH solution were added to a solution of ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinate (430 mg, 1.31 mmol) in 25 ml of methanol, and afterwards stirred for 2 hours at 60° C. The reaction mixture was subsequently evaporated to dryness, mixed with water and neutralized by adding 2N HCl. Filtration with suction and drying the precipitate formed resulted in 356 mg of the acid as yellow amorphous solid.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[CH3:47][C:48]1[C:53]([C:54]([OH:56])=O)=[C:52]([CH3:57])[N:51]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[N:49]=1.[N:68]1([CH:83]2[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]2)[CH2:73][CH2:72][CH:71]([O:74]C(=O)C2C=CC=CC=2)[CH2:70][CH2:69]1>>[CH3:57][C:52]1[C:53]([C:54]([N:86]2[CH2:85][CH2:84][CH:83]([N:68]3[CH2:73][CH2:72][CH:71]([OH:74])[CH2:70][CH2:69]3)[CH2:88][CH2:87]2)=[O:56])=[C:48]([CH3:47])[N:49]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:65])([F:66])[F:67])[CH:59]=2)[N:51]=1
Reactant: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B, 4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (intermediate 5) was converted into its acid chloride, reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester (example 22) and subsequently saponified to give the title compound as colorless solid. MS: 463.3 (MH+).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:5]([O:4][CH2:3][CH:2]([F:1])[F:19])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCC(F)F
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)ccc1OCC(F)F
Reaction time: 6.5 h

Procedure:
A mixture of ethyl 2-(2,2-difluoroethyl)oxy-5-nitro-benzoate (600 mg, 2.18 mmol) and 80 mg 10% Pd/C in 30 mL MeOH was stirred for 6.5 h under an atmosphere of hydrogen (3 bar). After filtration and concentration i. vac. the subtitle compound was obtained. Yield: 500 mg, (94%). MS [M+H]+=246; TLC: Rf=0.2 (silica gel, DCM:EtOH 99:1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5].C(=O)([O-])[O-].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.O>[CH3:2][O:3][C:4]([CH:6]1[CH:11]([NH2:30])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: COC(=O)C1CN(Cc2ccccc2)CCC1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 25° C. solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride (2.97 g, 10 mmol) in MeOH (10 mL) was added MP-Carbonate (12 g, 30 mmol, 2.54 mmol/g). After shaking at 25° C. for 1 h, the solution was filtered. To the resultant solution was added ammonium acetate (7.71 g, 100 mmol). After stirring at 65° C. overnight, sodium cyanoborohydride (610 mg, 10 mmol) was added into the resultant mixture and the mixture further stirred for 2 h at 50° C. The solution was then concentrated in vacuo to give a solid. The resultant solid was dissolved in water (100 mL) and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product 4-amino-1-benzyl-piperidine-3-carboxylic acid methyl ester (6) as a mixture of diastereomers. LCMS showed m/z: 249 (M+H)+. This material was used without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:6]([CH3:12])([CH3:11])[C:7](OC)=[O:8])#[N:5]>CCO.C(OCC)C>[C:4]([C:6]([CH3:12])([CH3:11])[C:7]([NH:2][NH2:3])=[O:8])#[N:5]
Reactant: NN
Reactant: COC(=O)C(C)(C)C#N
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)C(=O)NN
Yield: 39.3 %

Procedure:
Hydrazine hydrate (1.8 mL, 35 mmol) was added to a solution of methyl 2-cyano-2-methylpropanoate (5.0 g, 35.0 mmol) in EtOH (5 mL), and the reaction mixture was stirred at room temperature for 1 h (monitored by TLC, eluant petroleum ether:EtOAc 7:3 v/v). The reaction mixture was diluted with diethyl ether and the precipitate formed was filtered. The clear filtrate was concentrated under reduced pressure to get 2-cyano-2-methylpropanehydrazide (1.75 g, yield 38%), which was carried through without further purification. MS (ESI) m/z: Calculated for C5H9N3O: 127.07. found: 128.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N(C(C)C)(C(C)C)CC>CN(C=O)C.C(Cl)Cl>[CH2:13]([NH:20][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To an ice bath cooled mixture of 5-bromo-2-methoxybenzoic acid (439 mg, 1.9 mmol) in 1:1 CH2Cl2:DMF (4 mL) was added benzylamine (0.228 mL, 2.1 mmol), EDCI (438 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol) and NEtiPr2 (0.496 mL, 2.85 mmol). The mixture was then stirred at room temperature until the reaction was complete. Extractive work up with ethyl acetate, washing with saturated aqueous NaHCO3, H2O, saturated aqueous KHSO4 and brine, gave the title compound (550 mg) after isolation which was carried forward without purification. LCMS (M+H)+ 320, 322.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][C@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:13][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11]1)([O-])=O.CC(O)=O>[Fe].O>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][C@H:14]([C:16]([F:17])([F:19])[F:18])[CH2:13][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2[N+](=O)[O-])C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.9 %

Procedure:
A mixture of tert-butyl [(3S,5R)-1-(3-nitropyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (1 g, 2 mmol), iron powder (0.57 g, 10 mmol), AcOH (16 mL) and water (2 mL) was stirred at room temperature for 1 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the resulting residue was diluted with EtOAc. The resulting mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1 M NaOH aqueous solution and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.9 g (100% yield) of the sub-title compound as a brown solid. LCMS calc. for C16H24F3N4O2(M+H)+: m/z=: 361.2. found: 361.1.