Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Br:19]N1C(=O)CCC1=O>ClCCl.[Fe](Cl)(Cl)Cl>[Br:19][C:13]1[S:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)cs1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1

Procedure:
1.94 g of the compound from Example 2A having a purity of 57% (3.87 mmol) are provided in 35 ml of dichloromethane, 6.04 g (33.9 mmol) of N-bromosuccinimide and a spatula tip of iron trichloride are added and the mixture is heated under reflux for 18 hours. The reaction mixture is concentrated, the residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 30:1), and 1.30 g (83% of theory) of the title compound are obtained.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[C:15]([C:27]([F:30])([F:29])[F:28])[CH:14]=1)=[O:11])(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)=[C:15]([C:27]([F:28])([F:30])[F:29])[CH:14]=1)=[O:11])#[CH:5]
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product (1.59 g, 3.3 mmol) obtained from Step 2, potassium carbonate (1.82 g, 13.2 mmol) and 20 ml methanol were mixed in a reactor, and stirred at room temperature under the protection of an inert gas atmosphere for 3 hours. After completion of the reaction, methanol was removed on a rotary evaporator and the mixture was extracted with ethyl acetate and water. The organic layers were combined, washed with a saturated NaCl solution, and dried over anhydrous Na2SO4. The organic solution was concentrated on a rotary evaporator, and the residue was purified by silica gel column chromatography, to give a yellow oily liquid.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][C:30]=3[F:31])[N:27]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:26]=[CH:25]4)=[C:17]([F:38])[CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.CCOC(C)=O>C1COCC1.O>[F:38][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[F:31])[N:27]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[N:26]=[CH:25]2)[NH2:14]
Reactant: Fc1cc(N=C(c2ccccc2)c2ccccc2)ccc1Oc1cc2cnn(C3CCCCO3)c2cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of N-(diphenylmethylene-3-fluoro-4-(6fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yloxy)aniline (1.45 g, 2.85 mmol) in THF (30 mL) and water (5 mL) is added 1N aqueous HCl (5.69 mL, 5.69 mmol). The reaction is stirred at RT for 2 hours. EtOAc is added and the mixture is washed with saturated aqueous NaHCO3 solution, saturated aqueous sodium chloride, dried over Na2SO4, filtered and evaporated. The residue is purified by chromatography eluting with DCM then EtOAc:hexane (1:1) to offer the desired product as a pale gel (0.53 g, 54% yield). MS (m/z): 346 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].C(O[C:35]([N:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49](O)=O)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:49][C:46]1[CH:45]=[CH:44][C:43]([CH:40]2[CH2:39][CH2:38][N:37]([CH3:35])[CH2:42][CH2:41]2)=[CH:48][CH:47]=1)[C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2]
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2
Yield: 69.4 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (60 mg) according to an analogous synthetic method to Example 337 described below, the title compound (35 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(OCc3ccccc3)c(Br)cc21
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.213 mmol) in dichloromethane (5 mL) was treated with benzyl bromide (0.072 g, 0.64 mmol), DBU (0.100 g, 0.64 mmol), and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (50 mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.081 g of a clear oil. MS calculated for C20H19BrF3NO2+H: 442, observed: 442.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][NH:34][C:33]3=[O:37])[CH2:28][CH:29]=2)=[N:11]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>[Cu].[Cu](I)I.[O-2].[Zn+2].C(OCC)(=O)C>[CH3:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:19]=[C:18]3[C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][NH:34][C:33]3=[O:37])[CH2:28][CH:29]=2)=[N:11]1
Reactant: Brc1ccncc1
Reactant: Cn1nnc(-c2ccc3[nH]cc(C4=CCN(CCN5CCNC5=O)CC4)c3c2)n1
Agent: I[Cu]I
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCN4CCNC4=O)CC2)cn3-c2ccncc2)n1
Reaction time: 4 h

Procedure:
4-Bromopyridine hydrochloride (4×2g) was added during one hour to a mixture of 1-[2-[4-[5-(2-methyltetrazol-5-yl)-1H-indol-3-yl]-1,2,3,6-tetrahydro-1-pyridinyl]ethyl]-2-imidazolidinone (4a) (5 g), potassium carbonate (9 g), copper powder (1 g), copper iodide (0.3 g), zinc oxide (0.3 g) and N-methyl-2-pyrrolidinone (NMP) (75 mL) at 140-150° C. Heating was continued for additional 4 hours. After cooling, ethyl acetate (500 mL) was added. Inorganic salts were filtered off. Water was added and the organic phase was worked up according to the standard procedure above. The remaining crude product was purified by column chromatography on silica gel, eluted with a 50:50:4 mixture of ethyl acetate, ethanol, and triethylamine. Yield 0.7 g of the title compound 5a. mp 177-178° C. 1H NMR (DMSO-d6) δ 2.55-2.65 (m, 4H), 2.75 (t, 2H), 3.20-3.30 (m, 6H) 3.40 (t, 2H), 4.45 (s. 3H), 6.25 (s, 1H), 6.30 (broad t, 1H), 7.75 (dd, 2H, 7.90-8.00 (m, 3H), 8.60 (s, 1H), 8.75 (d, 2H), MS m/z (%): 236 (MH2++), 272 (9%), 245 (17%), 142 (65%), 113 (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N:25]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:31]3[CH:30]=[C:29]4[C:34](=[CH:33][CH:32]=3)[N:25]=[CH:26][CH:27]=[CH:28]4)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1ccc2ncccc2c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2ccc3ncccc3c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 42.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with quinolin-6-ol (38 mg, 0.26 mmol) to give the title compound (27 mg, 42%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[CH:12][C:7]=2[C:6](=[O:24])[NH:5][CH2:4][C:3]1=[O:25].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C=O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:12][C:7]=2[C:6](=[O:24])[N:5]([CH2:30][C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:4][C:3]1=[O:25]
Reactant: CN1C(=O)CNC(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Reactant: ClCc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(Cc2ncccn2)C(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Reaction time: 0.83 h
Yield: 7.7 %

Procedure:
1-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (22.9 mg, 0.065 mmol) and NaH (15.6 mg, 0.650 mmol, 10.0 equiv.) were placed in a 0.5-2 mL Smith process vial. To the vial was added DMF (0.5 mL) followed by 2-(chloromethyl)pyrimidine hydrochloride (53.9 mg, 0.327 mmol, 5 equiv.) was added at room temperature. After stirring for 50 min, reaction was quenched with AcOH. Resulting mixture was filtered and purified via preparative reverse phase HPLC to give the title compound (2.2 mg) as a clear yellow film.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C@@H:17]([CH3:47])[C:18]([N:20]([CH2:41][CH:42](OC)OC)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([O:33][Si](CC)(CC)CC)[CH2:26]2)=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15].C([SiH](CC)CC)C.C(N(CC)CC)C>>[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:42][CH2:41][N:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:32][CH2:31][C:28]4([CH2:29][CH2:30]4)[C@H:27]([OH:33])[CH2:26]3)[C:18](=[O:19])[C@@H:17]2[CH3:47])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC[Si](CC)(CC)O[C@@H]1CN(CCCCN(CC(OC)OC)C(=O)[C@H](C)Nc2ccc(Cl)c(Cl)c2)CCC12CC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
Trifluoroacetic acid (255 mg, 2.24 mmol) was added at RT to a solution of (S)-2-(3,4-dichloro-phenylamino)-N-(2,2-dimethoxy-ethyl)-N-[4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-propionamide (92 mg, 0.15 mmol), then after 30 min triethylsilane (87 mg, 0.75 mmol) was added. The reaction mixture was stirred for 16 h, then cooled to 0° C. and treated with triethylamine (226 mg, 2.24 mmol). The ice bath was removed, then after 15 min the reaction mixture was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; CH2Cl2→CH2Cl2/MeOH/25% aq. ammonia solution 80:20:1) afforded the title compound (34 mg, 52%). Light yellow gum, MS: 440.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([N:6]([CH2:16][CH3:17])[C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[C:9]([CH3:15])[CH:8]=1)[CH3:5]>CO>[CH2:16]([N:6]([CH2:4][CH3:5])[C:7]1[N:12]=[C:11]([C:13]([NH:2][OH:3])=[NH:14])[CH:10]=[C:9]([CH3:15])[CH:8]=1)[CH3:17]
Reactant: NO
Reactant: CCN(CC)c1cc(C)cc(C#N)n1
Agent: Cl
Solvent: CO
Product: CCN(CC)c1cc(C)cc(C(=N)NO)n1
Reaction time: 18 h
Yield: 86 %

Procedure:
To a cold (0° C.) solution of potassium tert.-butylate (494 mg, 4.40 mmol) in methanol (10 mL), hydroxylamine hydrochloride (262 mg, 3.73 mmol) is added. The mixture is stirred for 30 min before 6-diethylamino-4-methyl-pyridine-2-carbonitrile (238 mg, 1.26 mmol) is added. Stirring is continued at rt for 18 h before the solvent is evaporated. The residue is dissolved in 1 N aq. HCl. The solution is extracted with EA. The pH of the aq. phase is adjusted to pH ˜9 by adding sat. aq. NaHCO3. The mixture is extracted with EA and the org. extract is dried over MgSO4, filtered, concentrated and dried to give 6-diethylamino-N-hydroxy-4-methyl-pyridine-2-carboxamidine (241 mg) as a yellow oil; LC-MS: tR=0.69 min, [M+1]+=223.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH2:23][C:24](N)=[O:25])[CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[OH:28]>[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH2:23][C:24]([OH:25])=[O:28])[CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)COc1ccc2c(c1)CCCC2NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: O=C(O)COc1ccc2c(c1)CCCC2NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
10 mmol of 5-(4-chlorobenzenesulphonylamino)-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide are heated under reflux in 12 ml of 2N KOH and 40 ml of MeOH for 6 hours. The methanol is stripped off, 30 ml of 1N KOH are added and the mixture is extracted by shaking twice with CH2Cl2. The H2O phase is brough to pH 2 with concentrated HCl and the precipitates is filtered off and dried thoroughly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:11]([CH3:27])=[C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])[N:13]=1.C(N(CC)CC)C.[F:42][C:43]([F:51])([F:50])[CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47].O>ClCCl>[F:42][C:43]([F:51])([F:50])[CH2:44][CH2:45][S:46]([O:34][C:31]1[CH:30]=[CH:29][C:28]([N:10]2[C:11]([CH3:27])=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:33][CH:32]=1)(=[O:48])=[O:47]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c(C(=O)Nc2ccc(C(F)(F)F)cn2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C(F)(F)F)cn2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxamide (136 mg, 0.27 mmol) and triethylamine (40 μl, 0.32 mmol) in dichloromethane (4.0 ml) were cooled to −78° C. 3,3,3-trifluoropropane-1-sulfonyl chloride (63 mg, 0.32 mmol) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. The organic phase was washed with NaHCO3, brine and dried with Na2SO4. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (88 mg, 49%) as a solid.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH:10]1[CH2:14][CH2:13][N:12](C=O)[CH2:11]1>O>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1
Reactant: O=CN1CCC(OC2CCCCO2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C1CCC(O[C@@H]2CCNC2)OC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of KOH (5 g) in water (50 ml) was added to 3-(tetrahydropyran-2-yloxy)pyrrolidine-1-carbaldehyde. The mixture was heated at 50° C. for approximately one hour, after which time GC analysis showed the reaction was complete. After cooling to room temperature, the product was extracted with DCM (3×50 ml). The organic phase was dried over MgSO4 and concentrated. The title compound was obtained in 100% yield, (8.5 g). GC analysis, RT 10.4 min, 96.6% purity. δH (CDCl3) 4.60-4.70 (1H, m), 4.35-4.45 (1H, m), 3.80-3.95 (1H, m), 3.40-3.60 (1H, m), 2.90-3.25 (4H, m), 1.40-2.05 (8H, m).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: [H][H]
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 90.8 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 90.8% of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 28 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 80%; melting point, 79° to 82° C.).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][N:21]=[C:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CS(O)(=O)=O.N.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>CO.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][N:21]=[C:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(C3C=CCCC3)cc2CC1
Agent: [Rh]
Agent: CS(=O)(=O)O
Agent: N
Solvent: CCO
Solvent: CO
Product: CC1=NCCn2c1cc1c2-c2ccc(C3CCCCC3)cc2CC1
Reaction time: 24 h
Yield: 37 %

Procedure:
3-Cyclohex-2-enyl-5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole (1.05 g) was dissolved in 100 ml of methanol and treated with 0.2 ml of methanesulphonic acid. After the addition of 100 mg of tris(triphenylphosphine)-rhodium-(I) chloride the mixture was hydrogenated at room temperature for 24 hours. The mixture was freed from solvent, treated with 100 ml of 10% ammonia solution and extracted three times with 100 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.95 g of yellow oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. After concentration to a volume of about 16 ml and addition of 30 ml of ethyl acetate there separated 0.57 g of yellow crystals which were recrystallized from an ethanol/ethyl acetate mixture (1:2). There was obtained 0.39 g (37%) of 3-cyclohexyl-5,6,10,11 -tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 165°-167° C. (dec.).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])=[CH:16][C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:27]([C:15]1[CH:16]=[C:17]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)c2ccccn2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 76.4 %

Procedure:
A solution of Example 151 (42 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT over night. The reaction mixture was neutralized to pH=4, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid (30 mg, 76%). 8.45 (d, 4.0 Hz, 1H), 8.24 (d, 8.0 Hz, 1H), 7.92 (s, 1H), 7.88 (t, 7.6 Hz, 1H), 7.67 (d, 8.0 Hz, 1H), 7.36 (t, 5.6 Hz, 1H), 7.23 (t, 7.6 Hz, 1H), 6.96 (d, 6.8 Hz, 1H), 6.67 (s, 1H), 2.77 (t, 7.6 Hz, 2H), 2.22 (t, 7.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 393 (M+H+).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:18])[C@@H:11]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Product: CCCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxooctyl)-2-oxazolidinone (5.51 g), prepared in Referential Example 61, and tert-butyl bromoacetate (17 ml), the desired compound (4.13 g) was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[O:19].Cl>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]([S:25]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[O:19]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine (2.0 g, 22.9 mmol) in THF (40 mL) was added diisopropylethylamine (12.0 mL, 68.9 mmol) and 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (6.0 g, 25.3 mmol). The resulting solution was stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was acidified with 3N HCl and partitioned between H2O (100 mL) and Ethyl acetate (100 mL). The layers were cut and the aqueous layer was extracted with Ethyl acetate (3×100 mL) and EtOAc:THF (1:1, 2×100 mL). The combined organic cuts were washed with a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure. Silica gel chromatography (Ethyl acetate:hexanes, 4:1) afforded 6.31 g (95%) of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 108-109° C. 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, 1H, J=2.4 Hz), 7.17 (d, 1H, J=2.4 Hz), 4.40 (brs, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.33-3.40 (m, 3H), 3.20-3.23 (m, 1H), 1.93-2.02 (m, 1H), 1.82-1.89 (m, 1H), 1.79 (brs, 1H). Anal. Calcd. for C11H16N2O5S, C, 45.82; H, 5.59; N, 9.72; S, 11.12. Found: C, 45.92; H, 5.63; N, 9.61; S, 11.24.