Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1>CN(C)C=O>[CH2:9]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[CH:8]=[CH:13][CH3:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCNc1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
In 30 ml of dimethylformamide, 1.4 g of anhydrous potassium carbonate and 1.0 g of 1-chloro-2l-butene were added to 1.6 g of 3-aminobenzotrifluoride, followed by stirring for 2 hours from 70° C. to 90° C. After potassium carbonate was filtered off, 100 ml of saturated saline were added and the resulting mixture was extracted with benzene. The extract was dried over anhydrous sodium sulfate, concentrated and then subjected to chromatography on a silica gel column (hexane/ethyl acetate: 35/1, v/v), whereby the intended compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][S:14][C:13]2=[O:18])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:20][CH:21]=O>C(O)C>[N:1]1[CH:20]=[CH:21][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])[C:2]=12
Reactant: Nc1ncccc1OCCCN1C(=O)CSC1=O
Reactant: O=CCCl
Solvent: CCO
Product: O=C1CSC(=O)N1CCCOc1cccn2ccnc12

Procedure:
To a solution of 4.01 g (15 mmol) of 3-[3-(2-aminopyridin-3-yloxy)propyl]thiazolidine-2,4-dione in 40 ml of ethanol, 15 ml of a 40% chloroacetaldehyde solution was added at 60° C., followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 2.92 g (66.8%, white powder) of the desired product.
Reaction SMILES: [CH3:1][N:2]([C:4]1[N:14]=[CH:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=O)[C:6]=2[CH:5]=1)[CH3:3].P(Cl)(Cl)([Cl:17])=O>C(N(CC)CC)C>[Cl:17][C:11]1[C:6]2[CH:5]=[C:4]([N:2]([CH3:3])[CH3:1])[N:14]=[CH:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1cc2c(=O)[nH]cnc2cn1
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(Cl)ncnc2cn1
Reaction time: 1 h

Procedure:
6-(N,N-Dimethylamino)-pyrido[3,4-d]pyrimidin-4-one (12 g) was carefully treated with phosphorus oxychloride (42 ml) and triethylamine (18 ml) at room temperature under N2. After 1 hour at room temperature and 1 hour at 50° C., the mixture was concentrated in vacuo, azeotroping with toluene, then taken up in ethyl acetate, washed with sodium bicarbonate solution, dried and concentrated in vacuo to give the title compound (10.34 g); δH CDCl3 9.13(1H,s), 8.74(1H,s), 6.69(1H,s), 3.25(6H,s).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O-:18])=O)[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C([N:23](CC)CC)C>CN(C=O)C>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=1)[C:16]([NH2:23])=[O:18])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(C(=O)[O-])cc(N2CCCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(N)=O)cc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-carbonylimidazole (114 mg, 0.70 mmol) was added to a DMF (3 mL) solution of methyl 5-(1-pyrrolidinyl)isophthalate (146 mg, 0.59 mmol), and stirred at room temperature for 1 hour. Ammonium chloride (94 mg, 1.76 mmol) and triethylamine (0.246 mL, 1.76 mmol) were added to it, and further stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the formed insoluble matter was taken out through filtration, washed and dried to obtain the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH2:9])=[S:8])([CH3:5])[CH3:4].Br[CH:11]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:13]=2[C:12]1=O>C(O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:13]2[C:12]3[N:9]=[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[S:8][C:11]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1
Reactant: CC(C)(CO)NC(N)=S
Reactant: O=C1c2ccc(Br)cc2OCCC1Br
Solvent: CCO
Product: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS(ESI+): 369.3
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:8][CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[N:29]1([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:25]([C:22]1[CH:21]=[C:7]([CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:23]=1[OH:24])[CH2:8][CH2:9][N:32]1[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=2)[CH2:30][CH2:31]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Reactant: CCOC(=O)Cc1ccc(CCN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)Cc1ccc(CCN2CCN(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1

Procedure:
A mixture of 13.9 g. (50.2 mmole) p-toluenesulphonic acid (3,5-di-tert.-butyl-4-hydroxyphenethyl)ester, 18.4 g. (45.6 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-phenylacetate, 6.3 g. potassium carbonate and 300 ml. butan-2-one is heated for 8 hours while stirring at reflux temperature. For protection against oxidation, the reaction is carried out under an atmosphere of nitrogen. After cooling, the inorganic precipitate is filtered off with suction, the filtrate is evaporated and the evaporation residue is taken up in diethyl ether. From the ether solution, the hydrochloride is precipitated with hydrogen chloride-containing diethyl ether. After recrystallisation from ethanol, there are obtained 16.4 g. (62% of theory) of the desired compound as hydrochloride; m.p. 247°-250° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[O:28])[NH2:26].[CH2:42]([O:49][N:50]1[C:56](=[O:57])[N:55]2[CH2:58][C@H:51]1[CH2:52][CH2:53][C@H:54]2[C:59](O)=[O:60])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:42]([O:49][N:50]1[C:56](=[O:57])[N:55]2[CH2:58][C@H:51]1[CH2:52][CH2:53][C@H:54]2[C:59]([NH:26][NH:25][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[O:28])=[O:60])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
HATU (3.3 g, 8.7 mmol) and tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (2.29 g, 9.42 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (2 g, 7.25 mmol) in CH2Cl2 (50 mL), followed by the addition of DIPEA (2.8 g, 21.8 mmol). The reaction mixture was stirred at 0° C. for 12 hrs then washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 1%-10% MeOH/CH2Cl2) to give tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate as a white solid. (2.2 g, 62%). ESI-MS (EI+, m/z): 502.2 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Oc1cc(C(F)(F)F)nc(-c2ccc(C(F)(F)F)nc2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxy-6-trifluoromethyl-2-(6-trifluoromethyl-3-pyridinyl)-pyrimidine (145 mg, 0.469 mmol) and phosphorus oxychloride (10 ml) was refluxed for 3 h. The mixture was cooled to room temperature and rotary evaporated to leave an oily residue. The residue was extracted with ethyl acetate (50 ml), washed with water (2×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated in vacuo to give a crude solid (80 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: COc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-Cyclopropylmethoxy-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A37) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:48]1([C@H:54]([NH2:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:56][C@@H:54]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:55])=[O:6]
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)c1ccc(-c2ccncc2)cc1Cl)c1ccccc1
Reaction time: 8 h
Yield: 70.74 %

Procedure:
A 20-ml scintillation vial was charged with a solution of 2-chloro-4-(pyridin-4-yl)benzoic acid in DMA (20.0 mg, 0.085 mmol, 1.0 eq), a solution of HATU in DMA (39.06 mg, 0.103 mmol, 1.20 eq), and triethylamine (28.83 μL, 0.205 mmol, 2.40 eq). The mixture was briefly shaken and a solution of (R)-1-phenylethanamine (14.52 mg, 0.1198 mmol, 1.40 eq) in DMA was added. The mixture was left to shake at room temperature overnight. The mixture was then concentrated in vacuo and dissolved in 1.4 ml of DMSO/methanol (1:1 v/v) and submitted for reverse phase purification to afford (R)-2-chloro-N-(1-phenylethyl)-4-(pyridin-4-yl)benzamide (27.30 mg, 70.74% yield).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=2.C[O-].[Na+]>CO>[C:1]1([C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: Cc1cc2ccc(C(=O)O)cc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Cyclohexanone (96 mL, 0.926 mol) was added to a stirred solution of methyl indole-6-carboxylic acid (50.0 g, 0.335 mol) in methanol (920 mL) at 22° C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl solution. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the title compound as a tan colored solid (80.9 g, 97.5% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([CH2:24][CH2:25][CH3:26])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47].CCOC(C)=O>C(Cl)Cl>[Br:47][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([CH2:24][CH2:25][CH3:26])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1cc(CBr)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
To a solution of 839 mg of the crude product from Step N in CH2Cl2 (20 mL) were added triphenylphosphine (525 mg, 2 mmol) and carbon tetrabromide (663 mg, 2 mmol) at 0° C. The solution was stirred at 0° C. for 1 hour and at rt for 15 hours. The solution was poured into EtOAc (100 mL). After the precipitate was removed, the filtrate was washed with H2O and brine, and dried over anhydrous MgSO4. Concentration afforded 302 mg of the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH:16]2[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:20][CH2:21]2)=[CH:12][CH:13]=1
Reactant: CN1CCC(OC(c2ccccc2)c2ccc(F)cc2)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccc(F)cc2)CC1
Yield: 86.6 %

Procedure:
A quantity of 92.9 g of ethyl chlorocarbonate was added dropwise to a solution of 50.2 g of (±)-4-[(4-fluorophenyl)phenylmethoxy]-1-methylpiperidine in 200 ml of toluene, and the resulting solution was refluxed for 8 hours. After cooling, the reaction solution was washed with hydrochloric acid and water, dried and concentrated to give 51.9 g of yellowish brown liquid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C:13](N(OC)C)=[O:14])[C@@H:10]([OH:19])[C@H:9]([OH:20])[C@H:7]2[N:8]=1)[CH3:2].C([AlH]CC(C)C)C(C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH:13]=[O:14])[C@@H:10]([OH:19])[C@H:9]([OH:20])[C@H:7]2[N:8]=1)[CH3:2]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)N(C)OC)O[C@@H]2S1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C=O)O[C@@H]2S1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In a dry sealed vial was added (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-methoxy-N-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide (70.00 mg; 0.23 mmol; 1.00 eq.) in toluene (1.00 ml) and tetrahydrofuran (1.00 ml). The clear solution was cooled to −78° C. before hydrido(diisobutyl)aluminum (962.81 μl; 1.00 M; 0.96 mmol; 4.20 eq.) was added slowly. The obtained solution was stirred at −78° C. for 3 h before the reaction was quenched by addition of 1 mL H2O at −78° C. The obtained mixture was stirred at this temperature for 5 min before it is warmed up to room temperature. The mixture was filtered and the obtained filtrated was dried with lyophilize to afford the title compound as white solid.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[C:30]([C:35]([O:37]C)=[O:36])[N:31]=[CH:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[C:30]([C:35]([OH:37])=[O:36])[N:31]=[CH:32]4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)cc2cn1
Temperature: 120 °C
Yield: 68.4 %

Procedure:
To a solution of methyl 7-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (54 mg, 0.099 mmol) in 2:1 tetrahydrofuran:methanol (1.5 ml) was added 1 N sodium hydroxide (0.15 mL, 0.15 mmol). The solution was heated in a microwave reactor to 120° C. for 500 seconds. The solution was concentrated under a nitrogen stream and 1 N hydrochloric acid (0.15 mL, 0.15 mmol) was added. The solution was further concentrated under a nitrogen stream. Water and ethyl acetate were added and a solid precipitated that would not dissolve. The water layer was removed and the resulting mixture was washed twice with water. The organic solvents were removed under vacuum and the resulting solid was dried at 45° C. under a nitrogen stream to afford 7-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (36 mg, 68%). 1H-NMR (400 MHz, DMSO-d6) δ 13.1 (br s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.22-8.13 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.61-7.51 (m, 3H), 6.96 (d, J=9 Hz, 2H), 4.94 (s, 2H), 2.51-2.45 (m, 1H), 1.12-1.13 (m, 4H). HRMS (ESI) C29H20Cl2N2O4 calculated: 531.0880 (M+H)+, found: 531.0872 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:27]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I4) (287 mg, 1.5 mmol) and DIPEA (0.314 mL, 1.800 mmol) were dissolved at 0° C. in dichloromethane (DCM) (15 mL). 2-chloro-4-fluorobenzoyl chloride (290 mg, 1.500 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo) dissolved in DCM (5 mL) was added dropwise and the solution stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with dichloromethane (3×50 mL) and the combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil (759 mg). The crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanol:dichloromethane (1:9)/dichloromethane) to afford crude product. Concentration of the waste afforded material which was also identified as product. Samples were combined to afford crude product. This was purified by MDAP, product containing fractions concentrated and loaded directly on to an SCX cartridge (Varian, 10 g). The column was washed with methanol and the product eluted with 2M ammonia methanol. The solvents were evaporated in vacuo to afford the desired product in 318 mg.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[CH2:11]([N:18]([CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]=[C:41]=[O:42])[CH:38]=2)[NH:33][C:32]=1[C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=1)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]3[C:41](=[O:42])[NH:3][N:2]=[N:1]3)[CH:38]=2)[NH:33][C:32]=1[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Agent: [Al+3]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nn[nH]c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.7 %

Procedure:
To a solution of freshly prepared aluminum azide (0.6 mmol in 6 niL dry tetrahydrofuran) was added 120 mg benzyl-{2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl } -(4-pyridin-3-yl-butyl)amine and the mixture heated to reflux on an oil bath. After 20 hours, the mixture was cooled to room temperature concentrated poured into a mixture of 1M sodium potassium tartarate and ice, stirred vigorously for 40 minutes then partitioned between ethyl acetate and water. The organic portion was washed successively with 1M sodium potassium tartarate, water and brine then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 88:12) gave the title compound (58 mg).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]#[N:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:17]>>[N+:1]([C:4]1[C:5]([C:14]([NH2:15])=[O:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A round bottom flask was charged with 3-nitro-5-(trifluoromethyl)picolinonitrile (910 mg, 4.19 mmol) and sulfuric acid (4192 μl, 4.19 mmol), and the mixture was stirred at 60° C. for 16 h. Upon cooling to RT the crude mixture was poured onto ice, and the resulting solids were filtered, washed with water and dried. 3-nitro-5-(trifluoromethyl)picolinamide (850 mg, 3.62 mmol, 86% yield) was isolated as a light yellow solid. LC/MS (ESI+) m/z=236.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1F
Product: CC(=O)NCCc1ccccc1F

Procedure:
In close analogy to the procedure described above, 2-(2-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([NH:15][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of tert-butyl 4-oxopiperidin-1-carboxylate (5.01 g) and p-toluidine (2.69 g) dissolved in tetrahydrofuran (50 mL) were added sodium triacetoxyborohydride (7.99 g) and then acetic acid (3.0 mL). The reaction solution was stirred for 2 days. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and it was extracted with ethyl acetate. The extract was washed in turn with water and saturated aqueous sodium chloride solution, and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was purified by chromatography (silica gel, 20% ethyl acetate/hexane) to give the title compound (6.49 g).