Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:13]1([C:19]2[CH:20]=[N:21][N:22]([C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][N:12]=3)[CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-n1cc(-c2ccccc2)cn1
Temperature: 130 °C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
A mixture of 3.6 g of ethyl 2-chloronicotinate (19.4 mmol), 1.3 g of 4-phenylpyrazole (8.12 mmol), 4.4 g of K2CO3, 40 mg of 18-crown-6 and 30 mg of KI in 30 ml of N,N-dimethylformamide was stirred at 130° C. for 6 hours. For workup, H2O was added and, after extraction with ethyl acetate, the organic phase was washed with H2O and sat. NaCl solution. The crude product obtained after drying and concentration of the solution was purified by chromatography on silica gel (eluent: CH2Cl2/methanol 1-10%). In total, 1.9 g of an oil were obtained, which crystallized completely on standing in a refrigerator.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:22])[CH2:16][CH:17](OC)OC)[CH:10]=[C:11]([F:13])[CH:12]=1>O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:8]=1[CH:17]=[CH:16][C:15](=[O:22])[NH:14]2
Reactant: COC(CC(=O)Nc1cc(F)cc(F)c1)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1ccc2c(F)cc(F)cc2[nH]1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 135.2 %

Procedure:
A solution of 70% H2SO4 was made up by adding chilled H2SO4 (70 ml) to chilled water (30 ml) ensuring the temp remained between 10-20° C. The acid was then slowly added to the water keeping the temperature between 10 and 20° C. Finely ground N-(3,5-difluorophenyl)-3,3-bis(methyloxy)propanamide (12 g, 49 mmol) was added to the chilled solution over 1 h and then stirred at 5° C. for 1.5 h. An ice-water mixture (100 ml) was added carefully, followed by water (400 ml). The mixture was stirred for 0.5 h then the solid formed was filtered off and dried in the vacuum-oven at 40° C. over the weekend. The solid was still wet so it was dried in the desiccator with P2O5 to afford the impure desired compound (12 g, 136%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Br:34][C:35]1[S:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1>>[Br:34][C:35]1[S:39][C:38]([C:40]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:41])=[CH:37][CH:36]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Br)s1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Br)s3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 5-bromothiophene-2-carbonyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 5-bromo-2-thienyl ketone as a yellow powder. APCI-Mass m/Z 670/672 (M+H). 1H-NMR (DMSO-d6) δ 1.67 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.05 (s, 3H), 4.11 (d, J=4.0 Hz, 2H), 4.30 (ddd, J=9.8, 4.2 and 3.9 Hz, 1H), 5.30 (t, J=9.8 Hz, 1H), 5.55 (t, J=9.6 Hz, 1H), 5.81 (t, J=9.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.47 (d, J=3.9 Hz, 1H), 7.53 (d, J=4.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.46 (s, 1H).
Reaction SMILES: COC1C=CC(COC([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:36])[C@@H:18]([OH:35])[CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH2:12]2)=O)=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([NH:21][CH2:20][CH2:19][C@H:18]([OH:35])[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:36])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: COc1ccc(COC(=O)N2CCN(C(=O)[C@@H](O)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC[C@H](O)C(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Yield: 99.8 %

Procedure:
A 1.32 g of 1-(p-methoxybenzyloxycarbonyl)-4-((2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyryl)piperazine was added to a mixture of 15 ml of trifluoroacetic acid and 1.35 ml of anisole, followed by 1 hour of reaction at room temperature. After removing trifluoroacetic acid by evaporation under a reduced pressure, a residue was adjusted to basic with sodium hydroxide and extracted with chloroform, and the organic layer was washed with water and dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography to yield 0.91 g of 1-((2S)-4-(p-nitrobenzyloxycarbonyl)amino-2-hydroxybutyryl)piperazine as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9][CH2:8][C:7](=[O:22])[C:6]=2[CH:23]=1.S(=O)(=O)(O)O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3cc(Cl)ccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCNc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
7-Chloro-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (5 g) is added to 90% (w/w) sulfuric acid (50 ml), and the mixture is stirred at 0° C. to 10° C. for 2.5 hours. The reaction mixture is added to a cool water (50 mL) and then is neutralized by gradually adding thereto a solution of sodium hydroxide (75 g) in an appropriate amount of water with attention to exothermal reaction. The reaction mixture is cooled to 25° C., and the resulting yellowish green suspension is extracted with toluene (50 mL), and the organic layer is separated, washed with water (25 ml×2) and dried over sodium sulfate. After filtering off sodium sulfate, the filtrate is concentrated under reduced pressure to give a pale yellow crystals. The crystals are subjected to azeotropic dehydration with toluene in order to remove a slight amount of water to give 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one having a moisture content of less than 100 ppm (2.5 g, yield 89%, M.p. 103-104° C.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:20]([C:21]=1[O:22]C)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3].Cl>CO>[ClH:1].[CH2:2]([N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3]
Reactant: CCN(CC)CCCNC(=O)c1c(OC)c2ccccc2n1-c1ccccc1
Agent: Cl
Solvent: CO
Product: CCN(CC)CCCNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
2.1 g of 2-[3-(N,N-diethylamino)propylaminocarbonyl]-3-methoxy-1-phenylindole hydrochloride are dissolved in 5 ml of methanol and mixed with 2.5 ml concentrated hydrochloric acid. The reaction mixture is boiled for 3 h under reflux and subsequently evaporated under vacuum. 1.66 g (82% of theoretical) 2-[3-(N,N-diethylamino)propylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride are obtained as an oily substance. IR: 1647 cm-1 (CO amide).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:20][C:15]1[CH:16]=[N:17][N:18]([CH3:19])[C:14]=1[C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (200 mg, 0.61 mmole), and N-bromosuccinimide (0.61 mmole, 1.0 eq) in 2 mL of DMF was stirred at 100° C. for 10 minutes in the Microwave. The mixture was quenched with water, extract with ethyl acetate, and dried in vacuo give the title compound as a yellow solid (200 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 3.53-3.64 (m, 2H), 3.78 (s, 3H), 4.38-4.49 (m, 2H), 7.11 (d, 1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.39 (d, 1H). Exact mass calculated for C12H11Br2N3O3 402.9, found 406.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)=[CH:13][N:12]=1.C(=O)=O.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S@@:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=3)[CH2:21][CH2:20]2)=[CH:13][N:12]=1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4F)nc3)CC2)n1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc([S@@](C)=O)cc4F)nc3)CC2)n1
Yield: 16.4 %

Procedure:
The racemic sulfoxide 2-[2-fluoro-4-(methylsulfinyl)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (prepared as in Example 176, 195 mg) was subjected to Chiral HPLC [column: Chiralpak AS-H, column mobile phase: 65% CO2: 35% (80% MeOH: 20% CHCl3) (2 mL/min), pressure 140 bar, temperature 30° C., 280 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (32 mg) was isolated as an off-white solid with Tr of 11.25 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]3=[N:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:31]([OH:34])[C:32]#[CH:33]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]3=[N:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cn2c1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cn2c1=O
Temperature: 90 °C
Yield: 58 %

Procedure:
To a solution of N-(4-chlorobenzyl)-7-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (Procedure 3, 500 mg), PdCl2(PPh3)2 (21 mg), and Et3N (0.73 mL) in anhydrous DMF (3 mL) is added propargyl alcohol (0.094 mL). The mixture is heated at 90° C. for 1 h, then allowed to cool to room temperature. The reaction mixture is placed under high vacuum to remove the DMF. The resulting solid is dissolved in CH2Cl2 and washed with water. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried (Na2SO4), filtered, and condensed to afford a solid. The crude solid is adsorbed onto silica and chromatographed (1% MeOH/CH2Cl2 (1 L), 1.5% MeOH/CH2Cl2 (1 L), and 2% MeOHICH2Cl2 (1.5 L)). Product-containing fractions are combined and concentrated to afford 243 mg (58%) of the title compound as a creme solid. Physical characteristics: m.p. 179-181° C.; 1H NMR (300 MHz, DMSO-d6) δ9.34, 9.07, 9.00, 8.10, 7.85, 7.36, 5.50, 4.54, 4.36; IR (drift) 3294, 1676, 1632, 1618, 1561, 1541, 1521, 1490, 1353, 1335, 1131, 1061, 1040, 842, 797 cm−1; MS (ESI+) m/z 368 (M+H)+; Anal. found: C, 61.96; H, 3.69; N, 11.44.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([NH2:30])[CH:17]=1)=[O:15]>N1C=CC=CC=1.O>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([NH:30][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH:17]=1)=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 4.7 g (32.8 mmol) of dimethylsulfamyl chloride in 5 ml of dry pyridine is added to 5.0 g (16.4 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone in 100 ml of dry pyridine at 0°-10° C. The reaction mixture is stirred in the cold overnight and then poured in water and extracted with ether. The ether extract is washed with water and extracted with dilute aqueous KOH. This basic extract is washed with ether, acidified with hydrochloric acid and extracted with methylene chloride. The dried organic extract is evaporated in vacuo to give 4-benzyloxy-3-dimethylsulfamoylaminophenyl 2-pyridyl ketone. Hydrogenation over PcO2 according to the procedure of Example 3 gives α-(4-hydroxy-3-dimethylsulfamoylaminophenyl)-2-piperidylcarbinol.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:8]=1)=[CH2:2].N#N>CO.[Pd]>[NH2:22][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][C:7]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:14][CH2:15]1
Reactant: C=Cc1ccc([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CCc1ccc(N)c(NC2CCN(C3CCOCC3)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a mixture of N-(5-ethenyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine D25 (416 mg, 1.26 mmol) and NH4HCO2 (792 mg, 12.6 mmol) in methanol (100 mL) was added, under a positive flow of N2, 10% Pd—C (200 mg, 0.189 mmol). The resulted mixture was stirred under room temperature for 1.5 hours and was then filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with saturated NaCl solution (2×100 mL), dried with Na2SO4, and concentrated in vacuo to yield the title compound (251 mg, 66% yield). MS (ESI): 304 [M+H]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]>CS(C)=O.CCOC(C)=O>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C@@H:19]1[CH2:2][C@H:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)/C=C/c1ccc2ccccc2n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1ccc2ccccc2n1
Reaction time: 0.5 h

Procedure:
To a solution of tri-methylsulfoxonium iodide (495 mg, 2.25 mmol) in DMSO (4 mL) was added NaH (90 mg, 2.2 mmol) and the resulting mixture was stirred for 30 min. At this time compound 79a (400 mg, 1.87 mmol) was added in one portion and the resulting mixture was stirred overnight. The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate (100 mL) and concentrated in vacuo to obtain a residue which was purified by flash column chromatography on silica gel (0-50% EtOAc-heptane) to afford compound 79b as a white solid. Mass spectrum (LCMS, ESI pos.) Calcd. For C14H13NO2 228.0 (M+H). found 228.2.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([N:21]([CH2:29][C@@H:30]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])C1C=CC=CC=1.P([O-])([O-])([O-])=O>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([N:21]([CH2:29][C@@H:30]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20]
Reactant: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(OCc3ccccc3)cccc12)c1cccnc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O)cccc12)c1cccnc1
Yield: 86.2 %

Procedure:
To a solution of tert-butyl (1R)-2-(7-(benzyloxy)-1H-indol-3-yl)-1-methylethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl) oxy) ethyl)carbamate (2.5 g, 4.06 mmol) in methanol (50 mL) are added a phosphate standard buffer (pH 6.86, 2.5 mL) and a 10% palladium on carbon (50% wet, 2.5 g), and the mixture is stirred at room temperature for 1.5 hour under hydrogen atmosphere. The reaction solution is filtered through celite, and the filtrate is evaporated under reduced pressure to remove the solvent. To the residue are added water and ethyl acetate, and the organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→3:2) to give the title compound (1.84 g, yield: 87%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>C(O)C>[Cl:16][C:17]1[N:22]=[C:21]([N:6]2[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]2)[CH:20]=[CH:19][N:18]=1
Reactant: O=CN1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
1-Formylpiperazine (38.5 g) and triethylamine (34 g) in ethanol (500 ml) were added slowly to a stirred solution of 2,4-dichloropyrimidine (50 g) in ethanol (2.5 ml) at room temperature. The mixture was stirred at room temperature for 24 hours then evaporated in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and the combined aqueous phases extracted with chloroform. The combined chloroform extracts were dried (Na2SO4), evaporated in vacuo and the residue was crystallized twice from ethyl acetate to give 2-chloro-4-(4-formylpiperazino)pyrimidine, (24 g), m.p. 125°-126° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N+:26]([O-:28])=[O:27])=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=2[CH:25]=1.[OH:29]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N+:26]([O-:28])=[O:27])=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=2[CH:25]=1)=[O:29]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccccn3)cc21
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCS(=O)c3ccccn3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(2-pyridylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14]O.OS(O)(=O)=O>O>[CH3:14][O:12][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:13]
Reactant: CO
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of 1-adamantanecarboxylic acid (572 gm.), methanol (2.2 liters), and H2SO4 (90 ml.) was refluxed 5 hours and then cooled to room temperature overnight. The reaction mixture was poured into 28 liters of water and extracted with chloroform (2 × 150 ml.) for each 3.5 liters of solution). The chloroform extracts were combined, washed with water, dried, and concentrated. The residual oil was distilled to give 476 gm. product (77.5% yield) b17 approx. 143°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[CH2:54][CH:53]2[CH:49]([CH2:50][NH:51][CH2:52]2)[CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:51]4[CH2:52][CH:53]5[CH2:54][CH2:47][CH2:48][CH:49]5[CH2:50]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CC2CNCC2C1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CC3CCCC3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3,4-(1,3-propanediyl)pyrrolidine (BetaPharm) to give the title product. LC-MS (ES+) 758 [(M+H)+].
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12](C(=O)C)[CH2:11]2)=[CH:6][CH:5]=1.Cl>C(O)C.O>[F:28][CH:2]([F:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(C)=O)C2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COCCc1noc(C2CNCC(c3ccc(CC(F)F)cc3)C2)n1

Procedure:
A solution of 45.0 mg (0.083 mmol, purity 72%) of the compound from Example 60A in ethanol (10.0 ml) was admixed with 69 μl (15 mg, 0.42 mmol) of concentrated hydrochloric acid. Subsequently, the mixture was stirred under reflux for 24 h, and the reaction solution was diluted with water and washed with diethyl ether. The aqueous phase was alkalized and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 36.3 mg (87% of theory, purity 70%)