Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16]O)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.S([Cl:31])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][Cl:31])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CCl)o1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methanol (760 mg, 2.95 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.53 mL, 3.82 mmol) followed by DMAP (36 mg, 0.30 mmol) and Ms-Cl (0.30 mL, 3.73 mmol). After stirring at 0° C. until reaction completion, the reaction was quenched with water (50 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-chloromethyl-oxazole as a yellow oil. The crude material (2.95 mmol) was dissolved in dry DMF (15 mL) and treated with NaN3 (205 mg, 3.01 mmol) at 80° C. for 40 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-azidomethyl-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole as a yellow oil. LC-MS-conditions 02: tR=1.12 min; [M+H]+=283.55.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15].N#N.N1C=CC=CC=1.[F:39][C:40]([F:46])([F:45])[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=1)=[C:2]([O:1][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:11]=[CH:10]2
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.25 h

Procedure:
Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone in CH2Cl2 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0° C. in an ice/brine bath. Add pyridine (1.3 equivalents). Add trifluoromethane sulfonyl chloride (1.2 equivalents) via syringe over 15 minutes. After 15 minutes, quench the reaction with H2O (10 volumes), wash with 1 N HCl (5 volumes), wash with 1.0 N NaHCO3, and dry over Na2SO4. Concentrate to give the title compound in quantitative yield. Use the product without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.[OH-].[K+].O.C([OH:27])C>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)Sc1ncccc1CC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ncccc1CC2=O
Temperature: 0 °C

Procedure:
The mixture of 100 mg of 2-(5,6-dihydro-6-oxo benzo[b]-pyrido[3,2-f]thiepin-9-yl)-propionamide, 170 mg of potassium hydroxide, 1.5 ml of water and 3 ml of ethanol was refluxed for 5 hours. After cooling, the solvent was distilled off to obtain the residue, to which was added ice-water and the resulting mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the solid substance, which was recrystallized from benzene to give 70 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]thiepin-9-yl)-propionic acid as pale yellow powder having a melting point of 150°-151° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:12]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=3[NH2:22])[C@@H:11]3[CH2:23][C@H:8]2[CH:9]=[CH:10]3)=[O:6])[CH2:3][CH2:2]1.[Cl:24][C:25]1[N:26]=[C:27]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:28][C:29]=1[CH:30]=O.C([O-])(=O)C.[NH4+]>>[CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:12]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]4[NH:21][C:30]([C:29]5[S:28][C:27]([N:32]6[CH2:33][CH2:34][O:35][CH2:36][CH2:37]6)=[N:26][C:25]=5[Cl:24])=[N:22][C:15]=34)[C@@H:11]3[CH2:23][C@H:8]2[CH:9]=[CH:10]3)=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Reactant: Nc1ncc(Cl)c(N[C@H]2[C@@H](C(=O)NC3CC3)[C@@H]3C=C[C@H]2C3)c1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(NC1CC1)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 7.1 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid cyclopropylamide (200 mg, 0.6 mmol), 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (0.17426 g, 0.74892 mmol), and Ammonium acetate (92.439 mg, 1.1992 mmol) were reacted to produce 23.28 mg (7%) of the title compound. (300 MHz, DMSO-d6) 12.68 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 6.38-6.30 (m, 2H), 4.99 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 (m, 4H), 2.84 (s, 1H), 2.76 (s, 1H), 2.66 (m, 1H), 2.23 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.38 (d, J=8 Hz, 1H), 0.63 (m, 2H), 0.37 (m, 2H). MS=547 (M+H), HPLC: 2.72 min. (G Method)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[C:27](O)(=[O:30])[CH2:28][OH:29]>>[OH:30][CH2:27][C:28]([NH:1][CH2:2][CH:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)=[O:29]
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Reactant: O=C(O)CO
Product: Cc1cc(-c2nc(-c3ccc(C(O)CNC(=O)CO)cc3)no2)nc(NC(C)C)n1

Procedure:
The title compound is prepared in analogy to Example 127 using rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (Example 144) and glycolic acid; LC-MS: tR=0.81 min; [M+H]+=413.03.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]CC)=[O:18])[N:3]2[CH:6]([O:7]/[C:8]/1=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:4]2=[O:16].[OH-].[Na+:23]>C1COCC1>[CH3:1][C:2]1([C:17]([O-:19])=[O:18])[N:3]2[CH:6]([O:7]/[C:8]/1=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:4]2=[O:16].[Na+:23]
Reactant: CCOC(=O)C1(C)/C(=C/c2ccccc2)OC2CC(=O)N21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C(=O)[O-])/C(=C/c2ccccc2)OC2CC(=O)N21
Reaction time: 2 h
Yield: 82 %

Procedure:
Ethyl (Z)-2-methyl-3-benzylidene-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate (0.05 g, 0.174 mmole) was dissolved in 2 ml THF/2 ml H2O, ice cooled and treated with 1 N NaOH (0.174 ml). After 2 hours the solution was ether washed, brought to pH 7 with dil. HCl and freeze dried to yield the title compound (82%) as a off-white solid. νmax (KBr): 1772, 1673, 1600, 1390, 1208, 1034 cm-1. δ(D2O-ref HOD=4.45δ); 1.64 (s, 3H, 2-CH3), 2.88 (d, J=17 Hz, 1H, C6-H trans to C5-H), 3.30 (dd, J=17 and 2.5 Hz, 1H, C6-H cis to C5-H), 5.40 (s, 1H, =CH-), 5.58 (d, J=2.5 Hz, 1H, C5-H), 7.0-7.6 (m, 5H, Ph). λmax (EtOH): 270 nm (ε=18380).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+].Cl>>[CH3:4][C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(OCC(=O)O)cc2)cc1

Procedure:
2.0 g. 4-(1,1-Dimethylethyl)-N-[4-(ethoxycarbonylmethoxy)-phenyl]-benzamide (Example 31) are heated in 20 ml. 2N aqueous sodium hydroxide solution, then acidified with concentrated hydrochloric acid, filtered off with suction and washed with water. After recrystallisation from ethyl acetate, there is obtained 1.2 g. (65% of theory) of the title compound; m.p. 179°-181° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][C@H:13]([CH3:16])[CH2:12][N:11]1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:9][C@H:10]1[CH2:15][N:14]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C@H:13]([CH3:16])[CH2:12][N:11]1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1
Reactant: O=Cc1cccnc1
Reactant: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1Cc1cccnc1
Yield: 84 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(2S,5R)-2,5-dimethyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 84% yield.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[C:16]1([C:3]2[C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][C:23]([F:35])([F:34])[F:22])=[CH:26][CH:27]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(OC(F)(F)F)cc3)nc2c1
Yield: 47.9 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-(trifluoromethoxy)phenylboronic acid (89.6 mg, 0.43 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 57 mg (47%) of 2-phenyl-3-(4-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[N:19]1([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: NCCCCN1CCCC1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN3CCCC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and 4-(pyrrolidin-1-yl)butan-1-amine (Step 3), the title compound was obtained; MS (Found M+1=384).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C@H:7]([NH:9][CH2:11][CH2:12][CH2:13][OH:14])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@@H](NCCCO)c1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
To a solution of (R)-1-phenylethanamine (364 g, 3.00 mol) in water (43.7 ml) was added 3-chloropropan-1-ol (142 g, 1.50 mol) at room temperature. The mixture was stirred at 100° C. for 5 hours. The resulting mixture was cooled to 0° C. and basified with saturated aqueous potassium carbonate. The organic layer was extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The crude product was distilled under reduced pressure to remove excess (R)-1-phenylethanamine. The residue was diluted with chloroform and activated carbon was added to the solution. The mixture was refluxed for one hour and filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford (R)-3-(1-phenylethylamino)propan-1-ol as pale yellow oil (224 g, 83%).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@@H:45]1[C@@H:50]([CH2:51][O:52]C(=O)C2C=CC=CC=2)[O:49][C@H:48]([O:61][C@@H:62]2[C@@H:100]([CH2:101][O:102]C(=O)C3C=CC=CC=3)[O:99][C@@H:65]([O:66][NH:67][C:68](=[O:98])[CH2:69][O:70][CH:71]3[CH2:95][CH2:94][C@@:93]4([CH3:96])[CH:73]([CH2:74][CH2:75][C@@H:76]5[C@@H:92]4[CH2:91][CH2:90][C@@:89]4([CH3:97])[C@H:77]5[CH2:78][CH2:79][C@@H:80]4[C@H:81]([CH3:88])[CH2:82][CH2:83][CH2:84][CH:85]([CH3:87])[CH3:86])[CH2:72]3)[C@H:64]([O:111]C(=O)C3C=CC=CC=3)[C@H:63]2[O:120]C(=O)C2C=CC=CC=2)[C@H:47]([O:129]C(=O)C2C=CC=CC=2)[C@H:46]1[O:138]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.C1COCC1>[C@H:11]1([O:44][C@@H:45]2[C@@H:50]([CH2:51][OH:52])[O:49][C@H:48]([O:61][C@@H:62]3[C@@H:100]([CH2:101][OH:102])[O:99][C@@H:65]([O:66][NH:67][C:68](=[O:98])[CH2:69][O:70][CH:71]4[CH2:95][CH2:94][C@@:93]5([CH3:96])[CH:73]([CH2:74][CH2:75][C@@H:76]6[C@@H:92]5[CH2:91][CH2:90][C@@:89]5([CH3:97])[C@H:77]6[CH2:78][CH2:79][C@@H:80]5[C@H:81]([CH3:88])[CH2:82][CH2:83][CH2:84][CH:85]([CH3:86])[CH3:87])[CH2:72]4)[C@H:64]([OH:111])[C@H:63]3[OH:120])[C@H:47]([OH:129])[C@H:46]2[OH:138])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@H:10]1[OH:9]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)NO[C@@H]5O[C@H](COC(=O)c6ccccc6)[C@@H](O[C@H]6O[C@H](COC(=O)c7ccccc7)[C@@H](O[C@H]7O[C@H](COC(=O)c8ccccc8)[C@@H](OC(=O)c8ccccc8)[C@H](OC(=O)c8ccccc8)[C@H]7OC(=O)c7ccccc7)[C@H](OC(=O)c7ccccc7)[C@H]6OC(=O)c6ccccc6)[C@H](OC(=O)c6ccccc6)[C@H]5OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)NO[C@@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
Amide 132 (345 mg, 175 μmol) was dissolved in MeOH/THF 1:1 (16 mL). NaOMe (500 μL of a 6M solution) was added and the solution was stirred at room temperature for 24 hrs. The mixture was neutralized with acidic resin and the solution filtered before the solvent was evaporated to yield the white solid product which was triturated with EtOAc and the solvent decanted (×3). The solid was dried under vacuum to yield 124 mg of the white solid product (76%) which was reacted on without further purification or characterisation.
Reaction SMILES: [Cl-].[C:2]([CH:4]1[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>ClCCl>[CH2:17]([S:19]([N:7]1[CH2:8][CH2:9][CH:4]([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:21])=[O:20])[CH3:18]
Reactant: N#CC1CC[NH2+]CC1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(C#N)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyanopiperidinium chloride (13, 5 g, 45.4 mmol) dichloromethane (150 ml) and triethylamine (18.98 ml, 136 mmol). To the reaction was added dropwise ethanesulfonyl chloride (4.56 ml, 45.4 mmol) and the solution stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)piperidine-4-carbonitrile (14) as a white solid. MS 203 (M+1)
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[Br:15]N1C(=O)CCC1=O>ClCCl>[Br:15][C:5]1[N:4]([CH:12]([CH3:13])[CH3:14])[N:3]=[C:2]([OH:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cn(C(C)C)nc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(O)nn(C(C)C)c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.2 %

Procedure:
Ethyl 3-hydroxy-1-isopropylpyrazole-4-carboxylate (10.5 g) was dissolved in dichloromethane (100 mL) and to the stirred solution was added N-bromosuccinimide (14.1 g) under ice cooling. The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give 5.9 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]CC)=[O:16])[C:9]2=[O:20])=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:20])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 90C (0.40 g, 1.07 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.21 g, 8.57 mmol) in water (5 mL) was added and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and then concentrated to give the title compound. MS (DCI) m/z 346 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]1[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[CH2:23][CH2:24]1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2n1CCCl
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2n1CCN1CCOCC1

Procedure:
0.31 g. of 1-(2-chloroethyl)-2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole are boiled for 12 hours with 0.18 g. of morpholine in 50 ml. of dioxane. By evaporation and preparative thin-layer chromatography of the mixture, 50 mg. of 1-(2-morpholinoethyl)-2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole is obtained, the hydrochloride of which has a melting point of 237° C.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][O:34][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]=1[CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:40])=[O:5])(=[O:14])=[O:13]
Reactant: CN(C)CCOc1ccc2ccccc2c1CCOc1ccccc1S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOc1ccc2ccccc2c1CCOc1ccccc1S(=O)(=O)NC(C=O)CC(=O)O
Yield: 18.2 %

Procedure:
3-(2-{2-[2-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4-oxo-butyric acid tert-butyl ester (190 mg, 0.33 mmol) was stirred with trifluoroacetic acid (0.4 mL) in CH2Cl2 (1.2 mL) at room temperature for 1 h. Analytical HPLC analysis indicated the reaction was complete. The reaction mixture was concentrated. Residual trifluoroacetic acid was azeotroped with toluene. The crude product was purified by preparative HPLC to give 3-(2-{2-[2-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4-oxo-butyric acid (31 mg, 0.060 mmol) as a white solid in 18% yield. MS (APCI) m/z 515.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:6][CH2:7][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]5[NH:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:3][CH2:4]2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To the solution (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the residue dissolved in dichloromethane (15 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to afford the title compound (27 mg, 28%) as white powder. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.63-0.81 (m, 4H), 0.97 (s, 3H), 1.23-1.43 (m, 5H), 1.51-1.82 (m, 9H), 1.83-1.95 (m, 3H), 2.06-2.29 (m, 2H), 2.81-3.00 (m, 2H), 2.98-3.14 (m, 2H), 3.33-3.64 (m, 4H), 3.70-3.88 (m, 1H). MS (M+1): 389.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([Cu])#[N:26].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:25]#[N:26])=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2ccc(Br)cc2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 12 (9.46 g, 27.2 mmol) in anhydrous DMF (12.6 mL) under Ar was treated with CuCN (2.92 g, 32.6 mmol, 1.2 equiv) and the mixture was warmed at reflux for 20 h. The reaction mixture was cooled to 25° C. and poured into 250 mL of H2O to which FeCl3 (5.29 g, 32.6 mmol, 1.2 equiv) was added with swirling. The solution was extracted with EtOAc (3×200 mL) and the combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated. Recrystallization from 20% EtOAc-hexane provided 13 (6.70 g, 9.00 g theoretical, 74%) as a white solid. Chromatography (SiO2, 4×20 cm, 10% EtOAc-hexane) of the crystallization mother liquors afforded additional 13 (2.00 g, 22%, 96% combined) as white solid: mp 125° C. (needles, EtOH); 1H NMR (CDCl3, 250 MHz) δ8.43 (d, 1H, J=8.7 Hz), 8.29 (s, 1H), 8.25 (s, 1H), 7.69 (dd, 1H, J=1.6, 8.7 Hz), 7.66 (s, 1H), 7.56-7.39 (m, 5H), 5.32 (s, 2H), 4.46 (q, 2H, J=7.2 Hz), 1.46 (t, 3H, J=7.1 Hz); 13C NMR (CDCl3, 62.5 MHz) δ165.9, 154.3, 135.9, 134.6, 132.3, 129.8, 128.6, 128.3, 128.2, 127.8, 127.5, 123.8, 123.2, 118.6, 110.7, 106.9, 70.5, 61.5, 14.3; IR (KBr) vmax 2994, 2226, 1711, 1577, 1502, 1284, 1252, 1093, 1029, 916, 827 cm-1 ; FABHRMS (NBA) m/z 332.1276 (M+ +H, C21H17NO3 requires 332.1287).