Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]2OCC[O:19]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1>C(O)=O>[Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2Cl)cn1
Solvent: O=CO
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Yield: 85.5 %

Procedure:
Using a method similar to Example 403, Part B, a reaction of 5-(2-chloro-4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide (0.263 g, 0.820 mmol) in 88% formic acid gives the title compound (0.194 g, 85.5%): TOF MS ES+ 277.0 (M+H)+, HRMS calcd for C13H10N2O3Cl 277.0380 (M+H)+, found 277.0378, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=10.3 min, 100% purity.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[N+:32]([C:35]1[CH:63]=[CH:62][C:38]([CH2:39][O:40][C:41]([CH:43]2[CH2:48][NH:47][CH2:46][CH2:45][N:44]2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:47]2[CH2:46][CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=3)=[O:50])[CH:43]([C:41]([O:40][CH2:39][C:38]3[CH:62]=[CH:63][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)=[O:42])[CH2:48]2)=[O:29])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 34.1 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 0.47 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.20 g of N,N'-carbonyldiimidazole and 0.70 g of 2-(4-nitrobenzyloxycarbonyl)-1-(4-nitrobenzyloxycarbonyl)piperazine, 270 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C>O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:32][CH2:33]2)[S:26][CH:27]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (225 mg, 0.835 mmol), 1-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsufoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulafate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (90.9 mg, 31.2%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
A solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (7.87 g, crude, ˜17.9 mmol) in dichloromethane (59 mL) and acetonitrile (59 mL) was cooled to −30° C. under argon. Triethylsilane (11.5 mL, 71.6 mmole) was added to the reaction solution followed by addition of boron trifluoride etherate (6.8 mL, 53.7 mmole) so that the temperature didn't exceed −10° C. After the addition was complete the reaction solution was stirred for additional 1.5 h and then quenched with 5% sodium bicarbonate until the pH reached 7.5. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×80 mL). The combined organic phases were washed with brine (2×80 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to provide 6.8 g of the title compound as a pale solid which was used for the next step without purification. Yield: 93%. Purity (LCMS-0013) 2.9 min, 82% (UV); MS ESI (m/z) 409[M+1]+, calc. 408.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH:13]([C:20]([OH:22])=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH3:3].C1C=CC2N(O)N=NC=2C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2.CCN(C(C)C)C(C)C>C1COCC1>[CH2:2]([O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH:13]([C:20]([O:22][C@@H:36]2[CH:37]3[CH2:40][CH2:41][N:34]([CH2:39][CH2:38]3)[CH2:35]2)=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=1)[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
3-[(Carboxy-phenyl-methyl)-amino]-benzoic acid ethyl ester hydrochloride (I66) (161 mg, 0.48 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (218 mg, 0.57 mmol), and HOBT (88 mg, 0.57 mmol) are dissolved in dry THF (10 mL). (R)-Quinuclidin-3-ol (61.0 mg, 0.48 mmol) and DIPEA (0.17 mL, 0.96 mmol) are added and the mixture is stirred under inert atmosphere overnight. THF is evaporated and the crude residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The recovered organic layer is dried (Na2SO4), filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=95/5) to afford the title compound as a yellow oil (154 mg, 79% yield, mixture of diastereoisomers).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-])=O)(=[O:3])[CH3:2].CO>[Fe].O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[NH2:15])(=[O:3])[CH3:2]
Reactant: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COCSc1ccc(NC(C)=O)c(N)c1

Procedure:
1.5 G. of 1-acetamido-2-nitro-4-methoxymethylthiobenzene, also prepared according to Example VIII, is treated for 4 hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. of iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated to afford 1-acetamido-2-amino-4-methoxymethylthiobenzene.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (1.24 g, 4.80 mmol) was dissolved in 60 mL of dichloromethane followed by the addition of triethylamine (970 mg, 9.60 mmol) and carbobenzoxy chloride (0.90 g, 5.28 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-benzyloxycarbonylamino-2-hydroxy-propyl]piperazine-1-carboxylate 21a (1.45 g, yield: 76.0%) as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3]1.[OH-].[Na+]>C(O)C>[O:37]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:5][C:4]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 91.2 %

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 100; 0.195 g, 0.343 mmol) in ethanol (8 ml) was added NaOH (1.03 mmol in 0.5 ml water). The reaction mixture was stirred at room temperature for 70 min and then quenched by adding acetic acid (0.3 ml). The solvent was evaporated under reduced pressure and the residue was extracted with DCM/water. The organic layer was separated, washed with brine, dried and evaporated under reduced pressure to give the title compound 0.169 g (91%). NMR (500 MHz, CD3OD) 0.86 (t, 6H), 1.11–1.28 (m, 8H), 1.37–1.44 (m, 4H), 2.33 (s, 3H), 3.25 (s, 2H), 3.55 (s, 2H), 4.73 (s, 2H), 7.10–7.15 (m, 3H), 7.26 (s, 1H), 7.28–7.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:5]2=1.BrN1C(=[O:28])CCC1=O>C1COCC1.CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]3)[C:6](=[O:28])[NH:7][C:8]2=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)Nc1ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
A solution of tert-butyl 6-chloro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.500 g, 1.63 mmol) in 1:1:1 THF/AcOH/H2O (45 mL) at about 0° C. was treated with N-Bromosuccinimide (0.319 g, 1.79 mmol) portionwise over about 20 minutes. The resulting mixture was stirred for about 90 minutes at about 0° C. The mixture was then quenched by the addition of saturated Na2CO3 (100 mL) and extracted with DCM. The combined organics were washed with saturated NaHCO3 (2×) and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (20% EtOAc/Hexane) to yield tert-butyl 5-chloro-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.530 g, 100%). LCMS (APCI+) m/z 223, 225 [M+H−Boc]+; Rt=3.26 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[O:18][C@@H:17]2[CH2:19][OH:20])=[CH:12][CH:11]=1>O>[O:7]([C@@H:16]([C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)[C@H:17]([OH:18])[CH2:19][OH:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OC[C@H]1O[C@@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC[C@@H](O)[C@@H](Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A mixture of phenol (9.4 g), NaOH (1.33 g) and water (6.6 ml) was heated on a boiling water bath until the mixture became homogeneous. (2R, 3R)-3-Phenylglycidol (5.0 g) was added in small portions over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (3.99 g) in ice water (75 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a white solid. Recrystallization from methylene chloride gave white crystals (3.1 g) of (2R, 3S)-3-phenoxy-3-phenylpropane-1,2-diol.
Reaction SMILES: C(OC(=O)C=O)C.CCCC(N)CCC.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](=[O:36])[C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:27])=[CH:24][C:19]=2[O:18][CH2:17]1>>[CH3:32][CH2:31][CH2:30][CH:29]([NH:28][C:26](=[O:27])[C:25]([C:23]1[CH:22]=[CH:21][C:20]([OH:16])=[C:19]([O:18][CH3:17])[CH:24]=1)=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(CCC)NC(=O)C(=O)c1ccc2c(c1)OCO2
Agent: CCCC(N)CCC
Agent: CCOC(=O)C=O
Product: CCCC(CCC)NC(=O)C(=O)c1ccc(O)c(OC)c1
Yield: 34 %

Procedure:
N-(heptan-4-yl)-2-(4-hydroxy-3-methoxyphenyl)-2-oxoacetamide was prepared from 4-hydroxy-3-methoxy-phenyl)-oxo-acetic acid ethyl ester and 4-heptylamine by the same procedure described for the preparation of 2-(benzo[d][1,3]dioxol-5-yl)-N-(heptan-4-yl)-2-oxoacetamide. White crystals of the title compound (0.7 g, 34% yield) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: CN(C)CCN
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NCCN(C)C)cc3)cc12

Procedure:
N1-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)-N2,N2-dimethylethane-1,2-diamine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and N1,N1-dimethylethane-1,2-diamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.85 (m, 2H), 8.43 (d, 1H), 7.52 (s, 1H), 7.48 (m, 2H), 7.40 (m, 2H), 6.69 (m, 1H), 4.39 (m, 1H), 3.42 (m, 2H), 3.18-3.25 (m, 6H), 2.87 (s, 6H), 2.56 (s, 3H), 1.69 (d, 3H). LRMS [M+H]=428.2
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([CH2:17][C:18]#[CH:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[OH2:20]>CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([CH2:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O
Reactant: C#CCC1(C(=O)OCC)CCc2ccccc2C1=O
Solvent: CO
Product: CCOC(=O)C1(CC(C)=O)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
45 g (0.123 moles) of the compound having formula (XIV) obtained as described in the previous step (b), dissolved in 50 ml of methanol, are added to the suspension thus obtained. The reaction mixture is then left under stirring at room temperature for 18 hours and is subsequently hydrolyzed with water and extracted with various portions of ethyl ether. The ether extracts are joined, anhydrified on Na2SO4 and concentrated by evaporation at reduced pressure, obtaining at the end an oily red residue containing 43.5 g of the desired product having formula (XV) (65% purity upon GC analysis, 86% yield). Analyses show that both ethyl ester (45%) and methyl ester (55%) deriving from the transesterification of the product (XV) due to the use of methanol as solvent, are present. The product is not additionally purified.
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[CH3:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:8]3[N:9]=[C:5]([NH:4][C:32]([C:30]4[S:31][C:27]([CH3:26])=[CH:28][CH:29]=4)=[O:33])[S:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Agent: Br
Product: Cc1ccc(C(=O)Nc2nc(CC(=O)N3CCN(C4CCN(C)CC4)CC3)cs2)s1

Procedure:
In analogy to example 47.3, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide (example 47.2) was coupled with 5-methylthiophene-2-carboxylic acid, using general method D, to give 5-methyl-thiophene-2-carboxylic acid (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Light yellow solid. MS 448.4 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:18]=1.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[N:38]1([C:43]2[CH:44]=[C:45]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[NH2:46])[CH:42]=[CH:41][N:40]=[CH:39]1.NC1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:38]1([C:43]2[CH:44]=[C:45]([NH:46][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]4[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][N:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[CH:18]=4)[CH:4]=3)[CH:47]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:49]=2)[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cncc(CN2CCCC2)c1
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-methyl-3-{[5-(pyrrolidin-1-ylmethyl)pyridin-3-yl]ethynyl}benzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (prepared as above) is added along with 5 mole % of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 16 h an additional 0.2 equivalents of the aniline is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2×50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled, e.g. to 0° C., filtered, and the solid product is washed with cold ethyl acetate.
Reaction SMILES: C(O)C.[F:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1.[BH4-].[Na+].O>C(OCC)(=O)C>[F:4][CH:5]1[CH:10]([OH:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Reaction time: 1 h

Procedure:
To 6.5 mL of an ethanol solution containing 0.49 g of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate, 94 mg of sodium borohydride was added under cooling with ice, and the mixture was stirred for 1 hour. The reaction mixture was added with water and ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.42 g of a colorless oily substance, tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:18])([F:17])[CH2:11][CH2:12][B-](F)(F)F>>[F:9][C:10]([F:18])([F:17])[CH2:11][CH2:12][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: F[B-](F)(F)CCC(F)(F)F
Product: O=Cc1ccc(CCC(F)(F)F)s1
Yield: 89.5 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and 3,3,3-trifluoropropyltrifluoroborate (440 mg, 2.16 mmol) in place of hexylboronic acid to give 5-(3,3,3-trifluoropropyl)thiophene-2-carbaldehyde (244 mg, 90%). Used without further characterization.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:65])[C:12]([O:41][C@@H:42]1[O:63][C@@H:62]([CH3:64])[C@H:57]([O:58][C:59](=[O:61])[CH3:60])[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:43]1[O:44]CC1C=CC=CC=1)=[C:13]([C:27]1[CH:32]=[CH:31][C:30]([O:33]CC3C=CC=CC=3)=[CH:29][CH:28]=1)[O:14]2)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:64][C@@H:62]1[O:63][C@@H:42]([O:41][C:12]2[C:11](=[O:65])[C:10]3[C:15](=[CH:16][C:17]([OH:19])=[CH:18][C:9]=3[OH:8])[O:14][C:13]=2[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C@H:43]([OH:44])[C@H:52]([O:53][C:54]([CH3:55])=[O:56])[C@H:57]1[O:58][C:59]([CH3:60])=[O:61]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Oc2c(-c3ccc(OCc4ccccc4)cc3)oc3cc(OCc4ccccc4)cc(OCc4ccccc4)c3c2=O)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)[C@H](Oc2c(-c3ccc(O)cc3)oc3cc(O)cc(O)c3c2=O)O[C@H]1C

Procedure:
A suspension containing 0.26 g (0.29 mmol) of 10 and 0.10 g of Pd(OH)2/C in 10 mL of 1:1 THF-MeOH was purged with H2 and maintained under a H2 atmosphere for 1 h. The reaction mixture was then diluted with ethyl acetate, filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated under diminished pressure to give 1 as a tan solid: yield 0.14 g (94%); silica gel TLC Rf 0.35 (1:1:0.1 hexanes-ethyl acetate-methanol); [α]D17−106.5 (c 0.65, MeOH); 1H NMR (acetone-d6) δ 0.86 (d, 3H, J=6.3 Hz), 1.32 (br s, 1H), 2.01 (s, 3H), 2.06 (s, 3H), 3.54 (m, 1H), 4.48 (d, 1H, J=2.1 Hz), 5.12 (m, 1H), 5.23 (dd, 1H, J=9.9, 2.7 Hz), 5.61 (d, 1H, J=0.9 Hz), 6.32 (brs, 1H), 6.53 (brs, 1H), 7.09 (d, 2H, J=8.4 Hz), 7.90 (d, 2H, J=8.1 Hz), 9.44 (br s, 2H) and 12.62 (br s, 1H); 13C NMR (acetone-d6) δ 17.0, 20.2, 68.7, 70.5, 71.7, 94.1, 99.2, 101.5, 105.2, 115.9, 121.8, 131.1, 134.8, 157.5, 158.0, 160.5, 162.7, 164.6, 169.7, 170.1 and 178.5; mass spectrum (FAB), m/z 517.1345 (M+H)+ (C25H25O12 requires 517.1346).