Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.C([N:29]1[CH2:37][CH2:36][C:35]2[CH2:34][NH:33][CH2:32][C:31]=2[CH2:30]1)C1C=CC=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:32][C:31]5[CH2:30][NH:29][CH2:37][CH2:36][C:35]=5[CH2:34]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(CN2CCC3=C(CNC3)C2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNCC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
0.3 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.6 g of 3-benzyl-3,8-diazabicyclo[4.3.0] non-1(6)-ene hydrobromide were suspended in 30 ml of acetonitrile. 0.6 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) was added to the suspension. The reaction mixture was refluxed for 5 hours and then kept overnight at room temperature. The produced precipitate was filtered and dissolved in 30 ml of 5% acetic acid in ethanol. After adding 0.5 g of 10% palladium charcoal, the reaction mixture was stirred under the hydrogen stream for 6 hours and then filtered. The filtrate was concentrated under reduced pressure. 0.25 g of the title compound was obtained (yield 61%).
Reaction SMILES: [N:1]1[N:2]2[CH:8]([C:9]([O:11]CC3C=CC=CC=3)=[O:10])[CH2:7][CH2:6][C:3]2=[CH:4][CH:5]=1.[H][H]>[Pd].C(O)C>[N:1]1[N:2]2[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:3]2=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1CCc2ccnn21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1CCc2ccnn21
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A 100 mL round bottom flask under an atmosphere of nitrogen was charged with 0.600 mg (0.560 mmol) of 10 weight percent palladium on activated carbon and wet with 10 ml of ethanol. Next, a solution of 6.0 g (0.025 mol) of benzyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-6-carboxylate from step F in 40 mL of ethanol was added and the mixture placed under 1 atmosphere of hydrogen. The reaction was stirred for 3 h then filtered through a pad of Celite®. The pad was washed with 20 mL of ethanol and the filtrate was evaporated in vacuo to afford the title compound as a colorless solid (3.7 g, quantitative yield). 1H NMR (500 MHz, DMSO-d6): δ 11.90 (br s, 1H), 7.44 (s, 1H), 5.98 (s, 1H), 4.87 (dd, J=8.9, 3.7 Hz, 1H), 2.94-2.82 (m, 3H), 2.58-2.52 (m, 1H). LC-MS: m/z (ES) 153 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:19][CH2:18][C@H:10]3[N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH:13]=[CH:14][C@:9]3([CH3:20])[C:7]=2[CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:19][CH2:18][C@H:10]3[N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][C@:9]3([CH3:20])[C:7]=2[CH:8]=1
Reactant: CCCN1CC=C[C@]2(C)c3cc(OC)ccc3OC[C@@H]12
Agent: [Pd]
Solvent: CCO
Product: CCCN1CCC[C@]2(C)c3cc(OC)ccc3OC[C@@H]12

Procedure:
A solution of 1.5 g of a mixture of cis and trans-9-methoxy-10b-methyl-4-propyl-3,4a,5,10b-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine (example 3b) in 30 ml of ethanol is hydrogenated at 3 atmospheres pressure in the presence of 500 mg of 10% palladium on charcoal catalyst for 3 hours to give cis and trans-9-methoxy-10b-methyl-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine as a mixture of isomers.
Reaction SMILES: CO[CH:3]=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[CH2:14]([SH:16])[CH3:15]>C(O)C>[CH2:14]([S:16][CH:3]=[C:4]1[C:5](=[O:13])[O:6][C:7]([CH3:11])([CH3:12])[O:8][C:9]1=[O:10])[CH3:15]
Reactant: CCS
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCSC=C1C(=O)OC(C)(C)OC1=O
Yield: 60.8 %

Procedure:
5-(Methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (7 g, 38 mmole), described by Bihlmayer et al., supra, was suspended in ethanol (70 ml). The suspension was stirred vigorously while being subjected to the addition of ethanethiol (12.85 g, 200 mmole). The mixture was heated at reflux until all the starting material had been consumed, as indicated by thin layer chromatography (silica gel plates, 30% ethyl acetate in hexane). The volatile portion of the reaction mixture was removed by distillation under reduced pressure. The residue was purified by high pressure liquid chromatography (HPLC, 20% ethyl acetate in hexane, v/v). The purest fractions were combined. The solvent was removed under reduced pressure. The residue was crystallized to give 5.0 g of the title compound; mp 52°-54° C.; NMR (CDCl3) δ 1.45 (t, 3H), 1.7 (s, 6H), 3.02 (q, 2H), 9.0 (s, 1H); IR (CHCl3) 1720, 1700 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: ClCCNCCCl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Yield: 45.1 %

Procedure:
A mixture of 2-methoxy-5-nitro-phenylamine (16.8 g, 0.1 mol), bis-(2-chloro-ethyl)-amine hydrochloride (17.8 g, 0.1 mol) and potassium carbonate (69 g, 0.5 mol) in chlorobenzene (300 ml) was refluxed for 48 h, washed by water. The water phase was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, purified with flash chromatography on silica gel (CH2Cl2/MeOH) to give the desired product, 1-(2-methoxy-5-nitrophenyl)piperazine (10.7 g, 45%).
Reaction SMILES: [Na+].[O:2]=[C:3]1[CH:8]=[C:7]([C:9]([O-:11])=[O:10])[O:6][C:5]2[C:12]([CH2:20][CH2:21][CH3:22])=[C:13]3[C:18](=[CH:19][C:4]1=2)[CH2:17][CH2:16][CH2:15][CH2:14]3.[Na+].[OH:24]C1C2C(=O)C=C(C([O-])=O)OC=2C(CCC)=C2C=1CCCC2>>[OH:24][CH:14]1[C:13]2[C:18](=[CH:19][C:4]3[C:3](=[O:2])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][C:5]=3[C:12]=2[CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][CH2:15]1
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)[O-])oc13)CCCC2
Reactant: CCCc1c2c(cc3c(=O)cc(C(=O)[O-])oc13)CCCC2
Agent: [Na+]
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2O

Procedure:
The title compounds were made using the techniques of Examples 1 and 2, but substituting 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-carboxylic acid sodium salt for the 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-carboxylic acid sodium salt. the product compounds were identified and characterised by gas liquid chromatographic nuclear magnetic resonnance spectrometry and other analytical techniques.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[OH-].[K+:46].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:23][CH:24]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[K+:46]
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)[O-])c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1

Procedure:
3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid (1 eq.) is added to a reactor containing ethanol and stirred. A KOH solution in water (1.05 eq.) is added to the reactor and stirred at ambient temperature. After removal of the solvent, potassium 3-[5-(pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionate is obtained.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11](C(=O)C)[CH2:12][CH2:13][CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH:6]=1)C.O.Cl>C(O)C.[OH-].[Na+]>[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:33])=[O:3])[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cccc(N(CCCN2c3ccccc3CCc3ccccc32)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(NCCCN2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a solution of the above ester (1.0 g, 0.0023 mol) in ethanol (5 ml), 4N sodium hydroxide (0.6 ml) was added and the mixture was stirred at room temperature for 6 h and then left in a freezer overnight. The reaction mixture was allowed to warm up to room temperature and additional 4N sodium hydroxide (0.6 ml) was added. The mixture was stirred at room temperature for 3 h. Water and 4N hydrochloric acid (1.7 ml) were added, and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The residue was stripped twice with dichloromethane and dried in vacuo affording 0.5 g (59%) of the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:38]3[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
1-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) and 1-acetylpiperazine in an analogous manner as described in example 8. HR-MS (ES, m/z) calculated for C30H31N4O3Cl2 [(M+H)+] 565.1768, observed 565.1772.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([C:24]1[N:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(C1C=C(S(Cl)(=O)=O)C=CC=1OC)(C)(C)C>>[C:20]([C:24]1[N:29]=[C:28]([S:30]([N:17]2[CH2:16][CH2:15][N:14]3[CH2:19][C@H:11]([O:10][C:7]4[CH:6]=[N:5][C:4]([C:1]([CH3:2])=[CH2:3])=[CH:9][N:8]=4)[CH2:12][C@H:13]3[CH2:18]2)(=[O:32])=[O:31])[CH:27]=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: CC(C)(C)c1cccc(S(=O)(=O)Cl)n1
Agent: COc1ccc(S(=O)(=O)Cl)cc1C(C)(C)C
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(C)(C)C)n4)CCN3C2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 57, substituting the product from Example 202C (82 mg, 0.28 mmol) for the product from Example 27B, and substituting the product from Example 58B for 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride. The title compound was obtained as a colorless solid (79 mg, 62%). 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 9H), 1.78-2.06 (m, 2H), 2.17 (s, 3H), 2.31-2.49 (m, 2H), 2.50-2.62 (m, 1H), 2.61-2.74 (m, 1H), 2.91-3.06 (m, 2H), 3.69 (dd, J=9.92, 6.74 Hz, 1H), 3.85-3.96 (m, 1H), 4.02-4.13 (m, 1H), 5.22 (t, J=1.59 Hz, 1H), 5.32-5.42 (m, 1H), 5.77-5.81 (m, J=1.59 Hz, 1H), 7.51 (dd, J=7.54, 1.19 Hz, 1H), 7.71-7.84 (m, 2H), 8.15 (d, J=1.59 Hz, 1H), 8.20 (d, J=1.19 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[Br:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:12])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(-c2ccco2)cs1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(-c2ccco2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2-Amino-4-(2-furyl)thiazole (330 mg, 1.99 mmol) obtained in Step 1 was suspended in chloroform (4 mL), and N-bromosuccinimide (360 mg, 2.02 mmol) was added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford the entitled Compound g (438 mg, 90%).
Reaction SMILES: ClC(OCC)=O.C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C1COCC1.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1c2ccc(O)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate (3.2 mL, 33.4 mmol) were added to a solution of 5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 1, Step E) (5.6 g, 27.8 mmol) in THF/H2O (140 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was quenched by addition of an aqueous HCl solution (200 mL, 1.0 M) and the product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 2.7 g (35%) of the subtitle compound. 1H NMR (CDCl3 300 MHz) * 7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C16H21NO3+H: 276, observed: 276.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:32]([O:39][CH2:40][CH:41]=[O:42])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH:41]([OH:42])[CH2:40][O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(O)CO[Si](C)(C)C(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (Description 1; 10 g, 34.4 mmol) in tetrahydrofuran (100 ml) was cooled to −78° C. Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 50 ml, 50 mmol) was added dropwise and the mixture stirred, allowing to warm to room temperature over 1.5 hours. The orange solution was re-cooled to −78° C. and (tert-butyldimethylsilyloxy)acetaldehyde (10 g, 57.3 mmol) added. The mixture was allowed to warm to room temperature over 2.5 hours, then quenched with saturated aqueous ammonium chloride solution. The reaction mixture was partitioned between diethyl ether and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5-15% diethyl ether/dichloromethane, to give the title compound (12.4 g, 78%).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([CH3:15])=[CH:11][C:10]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1>C(O)C.[Pt]=O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)c1c[n+](C)ccc1-c1ccc(F)cc1
Agent: O=[Pt]
Agent: [Br-]
Solvent: CCO
Product: COC(=O)[C@@H]1CN(C)CC[C@@H]1c1ccc(F)cc1
Yield: 98.8 %

Procedure:
4-(4'-Fluorophenyl)-3-methoxycarbonyl-1-methylpyridinium bromide (15.90 g), prepared as in Example 1, in ethanol (250 ml) was hydrogenated at atmospheric pressure and 45° for 24 hours, in the presence of platinum oxide (0.5 g). Evaporation of the filtrate after removing the catalyst gave a dark oil which was partitioned between 10% sodium carbonate solution (100 ml) and dichloromethane (30 ml). After separation, the aqueous phase was extracted with dichloromethane (3×20 ml) and the organic solutions dried (potassium carbonate) and evaporated to give an off-white solid (12.1 g). Crystallisation from ethyl acetate gave the title compound as white crystals (8.32 g, 72%), m.p. 88°-89°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH2:13])[CH2:8][CH2:7]2.[CH:14]1([C:17]2[C:25]3[C:20](=[N:21][C:22]([O:27][CH2:28][C:29](O)=[O:30])=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:32])[N:18]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:14]1([C:17]2[C:25]3[C:20](=[N:21][C:22]([O:27][CH2:28][C:29]([NH:13][CH:9]4[C:10]5[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:12][CH:11]=5)[CH2:7][CH2:8]4)=[O:30])=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:32])[N:18]=2)[CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1)CCC2N
Reactant: Cc1cc(OCC(=O)O)nc2c1c(C1CC1)nn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCC2NC(=O)COc1cc(C)c2c(C3CC3)nn(C)c2n1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To the solution of 5-methoxy-indan-1-ylamine hydrochloride (92 mg, 0.46 mmol) and (3-cyclopropyl-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (building block A7, 120 mg, 0.46 mmol) in DMF (6 ml) were added DIPEA (0.24 ml, 1.38 mmol) and HATU (210 mg, 0.55 mmol) and the reaction was stirred at it for 30 min. The mixture was diluted with EtOAc, washed with aqueous bicarbonate solution and brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. Purification by preparative HPLC (Gilson GX-281, Waters Sunfire C18, 5 μm, 30×100 mm with guard column 19×10 mm, solvent A: water with 0.1% TFA, solvent B: acetonitrile, gradient 40-60% B in 15 min, flow reate 50 ml/min) gave the title compound as colorless solid (140 mg, 75%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.40 (d, 1H), 7.02 (d, 1H), 6.81 (s, 1H), 6.68 (d, 1H), 6.48 (s, 1H), 5.26 (dd, 1H), 4.80 (s, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 2.91-2.88 (m, 1H), 2.78-2.73 (m, 1H), 2.66 (s, 3H), 2.38-2.33 (m, 1H), 2.28-2.24 (m, 1H), 1.89-1.82 (m, 1H), 0.92-0.85 (m, 4H); LCMS RtH=3.095 min; [M+H]+=407.2]
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:9][C@@H:10]1[N:15]([C:16]2[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6])[CH3:3].C(O)(C(F)(F)F)=O.[Cl:46][C:47]1[N:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>C(Cl)Cl>[Cl:46][C:47]1[N:52]=[CH:51][C:50]([S:53]([N:12]2[CH2:13][CH2:14][N:15]([C:16]3[N:17]=[CH:18][C:19]([C:22]([OH:31])([C:23]([F:25])([F:26])[F:24])[C:27]([F:29])([F:30])[F:28])=[CH:20][N:21]=3)[C@@H:10]([CH2:9][N:4]([CH:2]([CH3:3])[CH3:1])[S:5]([CH3:8])(=[O:6])=[O:7])[CH2:11]2)(=[O:55])=[O:54])=[CH:49][CH:48]=1
Reactant: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A 5-mL vial was charged with tert-butyl (3R)-3-(((1-methylethyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.150 g, 0.259 mmol, step 2), TFA (1.0 mL, 13 mmol) and CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 30 min and then the volatiles were removed in vacuo. To the resulting residue was added CH2Cl2 (2 mL) followed by TEA (0.40 mL, 2.9 mmol). The mixture was stirred at room temperature for 10 min and then 6-chloropyridine-3-sulfonyl chloride (0.0627 g, 0.296 mmol, Organic Process Research & Development 2009, 13, 875) was added. After 10 min at room temperature, the mixture was concentrated and the crude product was purified by column chromatography (25 g of silica gel, 0 to 50% EtOAc in hexanes) to afford N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide (0.163 g) as a light-yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Solvent: CO
Product: N#CC1(N2CCOCC2)CCN(Cc2ccccc2)CC1

Procedure:
A solution of 5.25 g (23.8 mmol) 1-benzyl-4-hydroxy-piperidine-4-carbonitrile and 2.2 mL (25.2 mmol) morpholine in 30 mL MeOH was refluxed for 6 h. The mixture was evaporated to dryness i.vac., while the product was obtained in the form of crystals.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[CH:12](N=C(O)N(C(C)C)C(C)C)([CH3:14])[CH3:13]>C(#N)C>[CH3:13][CH:12]([O:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:14]
Reactant: CC(C)N=C(O)N(C(C)C)C(C)C
Reactant: COC(=O)c1sc(C)cc1O
Solvent: CC#N
Product: COC(=O)c1sc(C)cc1OC(C)C
Yield: 75.6 %

Procedure:
Methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (20.0 g, 116 mmoles) is dissolved in acetonitrile (450 mL) under argon. Triisopropylisourea (86.6 g, 465 mmoles) is added and the mixture stirred and heated under reflux. After 24 hours the mixture is cooled and the precipitate filtered off, rinsed with cold MeCN and discarded. The filtrate is stripped of solvent by rotary evaporator, then the excess triisopropylisourea is removed by distillation under reduced pressure. The remaining residue is dissolved in a small amount of ethyl acetate, cooled, filtered, and passed through a short column of silica gel. Evaporation of the effluent under reduced pressure leaves the product as an oil (18.8 g) sufficiently pure for further use.