Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].[H-].[Na+].CN(C)C=O.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>O>[CH:31]([N:17]([C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[O:7][C:6]([CH3:34])([CH3:35])[C:5](=[O:36])[N:4]([CH2:3][CH2:2][O:1][C:44](=[O:47])[CH2:45][CH3:46])[C:9]=2[CH:10]=1)=[O:16])[C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]1)([CH3:32])[CH3:33]
Reactant: CCC(=O)Cl
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCO)C(=O)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)OCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-hydroxyethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (150 mg) were added sodium hydride (16 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added propionic chloride (0.03 ml), and the mixture was further stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CN([CH:15]=[C:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21])C.CO>C(OCC)(=O)C>[OH:18][CH2:19][CH2:20][C:16]1[C:17](=[O:21])[N:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]2=[N:11][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CN(C)C=C1CCOC1=O
Reactant: Nc1nccc2ccccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c(CCO)cnc2c3ccccc3ccn12
Temperature: 200 °C
Yield: 75 %

Procedure:
A heterogenous mixture containing 14.4 g of 1-isoquinolinamine (0.1 m) and 14.12 g of dihydro-3-[(dimethylamino)methylene]-2(3H)-furanone was heated to 200° C. for 4 hours to yield a homogenous yellow orange solution which solidified upon cooling to ambient temperature. The solidified reaction mixture was titurated with methanol and ethyl acetate to yield 3-(2-hydroxyethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one as a tan solid (18.0 g; 75% yield) of the formula ##STR26## having a melting point of 185.2°-187.0° C. and the following elemental analysis:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[C:7](=[O:17])[C:6]=2[CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[S:9]2(=[O:11])=[O:10])[CH2:27][CH2:26]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 5-fluoro-2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)one 1,1-dioxide and 0.02 mol of 1-(2-pyrimidinyl)piperazine are stirred with 0.02 mol of K2CO3 in 150 ml of absolute DMF at 100° C. for 1 hour. The mixture is then evaporated. Water is added and the organic substance is taken up in methylene chloride. The dried CH2Cl2 phase is applied to a silica gel column and eluted with CH2Cl2 /CH3OH (95:5).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:21]=[N:22][N:23]([CH3:24])[C:3]=12.C(O)(=[O:27])C>O>[CH3:24][N:23]1[C:3]2[C:2](=[O:27])[C:11]3[CH:10]=[C:9]([CH2:12][C:13]4[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=4)[C:16]#[N:17])[CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:21]=[N:22]1
Reactant: Cn1ncc2nc3ccc(Cc4cccc(C#N)c4)cc3c(Cl)c21
Reactant: CC(=O)O
Solvent: O
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Temperature: 25 °C
Yield: 86 %

Procedure:
A suspension of 3-[(9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile (EXAMPLE 28, step 1, 729 mg, 2.19 mmol) in acetic acid (8 ml) and water (8 ml) was refluxed for 5 h. After cooling to room temperature, water (20 ml) was added and the precipitate was collected by filtration. This yellow solid was washed with water, ethanol and hexane to give 594 mg (86%) of the title compound as a yellow solid.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:41]=[CH:40][C:32]2[S:33][CH:34]=[C:35]([CH2:36][CH2:37][CH2:38][NH2:39])[C:31]=2[CH:30]=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[F:28][C:29]1[CH:41]=[CH:40][C:32]2[S:33][CH:34]=[C:35]([CH2:36][CH2:37][CH2:38][NH:39][CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[C:31]=2[CH:30]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: NCCCc1csc2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCc1csc2ccc(F)cc12)O3
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (151 mg, 0.669 mmol) and 3-(5-fluoro-benzo[b]thiophen-3-yl)-propylamine (140 mg, 0.335 mmol) in anhydrous dimethylsulfoxide (7 mL) was stirred at ambient temperature for three days without any apparent reaction occurring. The reaction was then heated at 40° C. for two days, resulting in complete conversion. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (35 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacua. Flash chromatography on silica gel (2/2/96 methanol/2 M ammonia in methanol/methylene chloride) afforded 90 mg (63%) of the title compound as a yellow viscous oil, which was converted to its fumarate salt as a yellow solid: mp 117-120° C.; MS (ES) m/z 423 [M+H]+; [α]D −29.1° (c 0.94, DMSO)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](N)[CH:20]=2)[CH:15]=[N:14]1.N([O-])=[O:24].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH:15]=[N:14]1
Reactant: O=N[O-]
Reactant: Nc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-aminoindazole [Compound No. 47] (10 g) in 50% sulfuric acid (30 g), a solution of sodium nitrite (3 g) in water (10 g) was added dropwise while cooling with ice, and the resultant mixture was stirred. After 1 hour, the mixture was added dropwise for 1 hour to 10% sulfuric acid heated at 100° C. to 110° C., and the resultant mixture was refluxed for 30 minutes. After completion of the reaction, the reaction mixture was cooled and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexaneethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxyindazole (6 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:6][CH:14]([OH:15])[C:13]([OH:17])=[O:16])=[O:5]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: O=CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(O)C(=O)O)c1c(F)cccc1F
Yield: 52.5 %

Procedure:
A mixture of 50 g (0.318 mol) of 2,6-difluorobenzamide, 32 g (0.349 mol) of glyoxylic acid monohydrate and 200 mL of acetone was refluxed for 5 h. The reaction was cooled and solvents evaporated to give a white solid. It was triturated with cold acetone to afford 38.56 g of a white solid: mp 125°-127° C. 1H-NMR (DMSO-d6)δ9.55 (d, 1H), 7.50 (m, 1H), 7.15 (t,2H), 5.45 (d,1H)
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[NH:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:33][C:30]4[CH:31]=[CH:32][NH:28][N:29]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Nc1cc[nH]n1
Reactant: CC(C)CNc1nc2ccccc2n2c(-c3ccc(C(=O)O)cc3)cnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: CC(C)CNc1nc2ccccc2n2c(-c3ccc(C(=O)Nc4cc[nH]n4)cc3)cnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
0.1 mmol 4-{4-[(2-methylpropyl)amino]imidazo[1,2-a]quinoxalin-1-yl}benzoic acid (1.0 mL, 0.1 M in NMP) (example 1.5), 0.2 mmol 1H-pyrazol-3-amine (1 mL, 0.5 M in NMP, 2 eq), 0.2 mmol HATU (1 mL, 0.5 M in NMP, 2 eq) and 0.4 mmol NMM (0.133 mL, 3 M in NMP, 4 eq) were combined, shaken at rt for 24 h and subjected to preparative HPLC to give 7.6 mg 4-{4-[(2-methylpropyl)amino]imidazo[1,2-a]quinoxalin-1-yl}-N-(1H-pyrazol-3-yl)benzamide (18%): UPLC-MS: RT=1.04 min; m/z (ES+) 426.5 [MH+]; required MW=425.5.
Reaction SMILES: CC[Mg+].[Br-].CCOCC.[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[C:20]#[N:21]>C1(C)C=CC=CC=1>[CH:10]([N:13]([CH:14]([CH3:16])[CH3:15])[C:20](=[NH:21])[C:19]1[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])([CH3:12])[CH3:11]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1c(F)cccc1F
Agent: CC[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=N)c1c(F)cccc1F)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A solution of EtMgBr in ether (8.0 mL, 3.0 M, 24 mmol) was added to a solution of diisopropylamine (2.50 g, 24.8 mmol) in toluene (60 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and 2,6-difluorobenzonitrile (3.34 g, 24 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 98%. The mixture was quenched with an aqueous NH4Cl solution (1%, 100 mL). The organic phase was separated from the aqueous phase and the latter was extracted with diethylether (200 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure giving 5.40 g (91%) of pure product. The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.2 (m, 1H), 6.8 (m, 2H), 5.5 (bs, 1H), 3.7 (bs, 1H), 3.4 (bs, 1H), 1.5 (bs, 6H), 1.0 (bs, 6H), by 13C NMR 75 MHz (CDCl3) δ (ppm): 158.9 (dd, J=248 Hz, J=8 Hz), 155.7, 130.1, 130.0, 129.8, 112.1, 112.0, 111.9, 111.852.0 (bs), 46.2 (bs), 21.3, 20.5 and by 19F (282 MHz) (CDCl3) δ (ppm) −114.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C(Cl)(Cl)Cl.CO>C(O)C>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([OH:4])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)CC[C@H]3[C@H]1C5
Reaction time: 8 h

Procedure:
To morphine free base (3 am, 10.5 mmol.) dissolved in absoTute ethanol (150 ml) palladium-on-activated carbon (5˜o) (1 am., 50 p.s.i.) was added. Reduction was carried out overnight (12-14 hours), in a Parr hydrogenator at ambient temperature. After confirmation of the quantitative conversion to 7,8-dihydromorphine by TLC, the ethanolic solution was filtered over Celite. The organic solvent ethanol was removed by rotary evaporation at reduced pressure, to afford 2.93 am. (97.2%) of dibydromorphine as an off-white glassy solid, homogeneous by TLC (CHCl3:MeOH (9:1), Rf=0.2). Elemental Analysis Calcd. for C17H21NO3:C, 71.08; H, 7.32; N, 4.88. Found: C, 71.11; H, 7.34; N, 4.91.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1.O>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:4]3[S:3][C:2]([Br:1])=[CH:6][CH:5]=3)[OH:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: Brc1ccc(Br)s1
Reactant: O=Cc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc2occc2c1)c1ccc(Br)s1
Reaction time: 0.67 h
Yield: 81 %

Procedure:
To a solution of 2,5-dibromothiophene (2.05 g, 8.48 mmol) in tetrahydrofuran (25 mL) was added n-butyl lithium (3.48 mL, 8.48 mmol) at −78° C., and the solution was stirred for 40 minutes. Then, benzofuran-5-carbaldehyde described in Preparation Example 175 (1.24 g, 8.48 mmol) was added to this reaction solution at −78° C., and the solution was stirred at room temperature for 75 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=3/1), and the title compound (2.11 g, 81%) was obtained as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[CH2:19][CH:20]([C:22]1[O:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH:23]=1)[OH:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[O:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23][CH:22]1[CH:20]([OH:21])[CH2:19][N:15]1[CH2:16][CH2:17][CH:12]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: OC(CCl)C1=COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(C3CCN(CC(O)C4COc5ccccc5O4)CC3)c2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 111.5 %

Procedure:
A mixture of 4.6 g of 4-(5-methoxy-[1H]-indol-3-yl)-piperidine, 4.3 g of α-(chloromethyl)-1,4-benzodioxin-2-methanol, 4.4 g of sodium carbonate, 3.3 g of potassium iodide and 25 ml of dimethylformamide was heated with stirring at 100° C for 24 hours under a nitrogen atmosphere and then the mixture was cooled and filtered. The filter was washed with dimethylformamide and the filtrate was evaported under reduced pressure to dryness. The residue was taken up in a 1--1 mixture of water and methylene chloride and the organic phase was recovered by decantation, was washed, dried and evaporated to dryness under reduced pressure to obtain 9.1 g of α-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-(5-methoxyl-[1H]-indol-3-yl)-1-piperidine-ethanol in the form of a mixture of 2 diastereoisomeric racemates in the form of a brown oil which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11]OS(C)(=O)=O)[O:7][C:6]=2[CH:17]=1.Br.[NH:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:20]1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:19]3[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]4[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20]3)[O:7][C:6]=2[CH:17]=1
Reactant: CS(=O)(=O)OC[C@H]1COc2ccc(F)cc2O1
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccc(F)cc4O3)C2)c1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
A mixture of methanesulfonic acid (R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester (51 mg, 0.19 mmol), (R*)-3-(piperidin-3-yl)phenol HBr (50 mg, 0.19 mmol) and NaHCO3 (33 mg, 0.39 mmol) in DMF (3.5 ml) was heated at 120° C. for 1.5 h. Water (10 ml) was added to the cooled mixture, which was then extracted with EtOAc (3×10 ml). The combined organic layers were washed several times with water and finally twice with brine. Drying (Na2SO4), filtering and evaporation of the solvent gave the crude product, which was recrystallised from EtOH to afford 24 mg of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:50][C:51]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=4)=[O:52])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=3)=[O:52])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
8.0 ml of trifluoroacetic acid and 160 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a suspension of 1120 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-piperazinecarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 1.75 ml of anisole, and the resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was repeatedly washed with diethyl ether by decantation and dried in vacuo, to afford 1.58 g of the title compound, as a powder.
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[ClH:1].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(F)ccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][CH:37]=[CH:36][C:24]=1[CH2:25][N:26]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:27]1=[O:35]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:32]([C:29]3[CH:30]=[CH:31][N:26]([CH2:25][C:24]4[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=4[O:22][CH3:21])[C:27](=[O:35])[CH:28]=3)=[O:33])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COc1ccccc1Cn1ccc(C(=O)O)cc1=O
Product: COc1ccccc1Cn1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1=O

Procedure:
1-(2-Methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(2-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C30H25ClN3O4 [(M+H)+] 526.2, obsd. 526.0.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.CS([C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:13]2[N:26]=[CH:27][N:28]=[C:12]2[N:11]=1)(=O)=O>O>[CH3:1][O:2][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:13]2[N:26]=[CH:27][N:28]=[C:12]2[N:11]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
62 mg of a sodium methoxide 28% methanol solution was added to a methanol 3 mL solution of 100 mg of 5-(methylsulfonyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, followed by stirring at room temperature for 5 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 85 mg of the desired product.