Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH:11]=[CH:12][CH:13]=1.[Cl:23][C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:23][C:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH:11]=[CH:12][CH:13]=1)=[O:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1csc(-c2cccc(OCCCCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(-c2cccc(OCCCCCOC(=O)Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(3-(5-hydroxypentyloxy)phenyl)thiazole-4-carboxylate (26), (32 mg, 0.10 mmol, 1.0 eq.) in ethyl acetate (1 mL) was added triphosgene (14 mg, 0.047 mmol, 1.4 eq) dissolved in a minimum amount of ethyl acetate, followed immediately by DIEA (26 μL, 20 mg, 0.15 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min, the precipitated DIEA hydrochloride was filtered off, and the filtrate evaporated to dryness in vacuo. The oily residue of crude compound 27 was used directly for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Reactant: NNCc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with benzylhydrazine (CAS Reg. No. 555-96-4) to give the title compound. MS (ESI): m/z=378.5 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CN(Cc2ccccc2OC)S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1CN(Cc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccc(O)cc1
Yield: 15 %

Procedure:
Methyl 4-((4-acetoxy-N-(2-methoxybenzyl)phenylsulfonamido)methyl)benzoate (crude) was dissolved in THF (1.0 mL) and treated with aqueous NaOH (1N, 2.0 mL, 2.0 mmol). The mixture was refluxed for an hour. Upon completion the THF was removed in vacuo and the resulting aqueous solution was acidified with 6 N aq HCl to a pH of ˜3. The aqueous phase was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse phase HPLC to afford 10.8 mg of the title compound (15% yield over two steps).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OC=C)=O)[CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:2]=1.[ClH:30]>O1CCOCC1>[ClH:30].[C:1]1([CH3:29])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:2]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3cccc(C)c3)(c3cccc(C)c3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CNCC32)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
(3aRS,7aRS)-7,7-Bis(3-tolyl)-2-vinyloxycarbonylperhydro-4-isoindolone (7.4 g) is treated with a 6N solution (39 cc) of hydrochloric acid in dioxane for 30 minutes at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue taken up with ethanol (100 cc). The solution is heated to 60° C. for 2 hours and stirred for 16 hours at 25° C., then concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified with isopropyl ether and the solid is washed, drained and dried. 7,7-Bis(3-tolyl)perhydro-4-isoindolone hydrochloride (6.36 g) is obtained in the form of a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: Brc1cncc(N2CCOCC2)c1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(N4CCOCC4)c3)cnc21
Temperature: 90 °C

Procedure:
In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-(5-bromo-pyridin-3-yl)-morpholine (228 mg, 0.94 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Argon for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Argon for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h. The reaction mixture is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is purified by flash silica gel column (MeOH/DCM 0 to 4% gradient, then 4%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and are extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 60 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.[C:30]([C:32]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:36]2[N:46]=[C:47]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:48]=[C:35]2[N:34]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=2)[C:33]=1[CH3:70])#[N:31]>CN(C=O)C>[CH2:52]([O:51][C:50](=[O:59])[N:49]([C:47]1[N:48]=[C:35]2[N:34]([C:60]3[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:67])[F:68])[CH:61]=3)[C:33]([CH3:70])=[C:32]([C:30]#[N:31])[C@@H:37]([C:38]3[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=3)[N:36]2[N:46]=1)[CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: BrCC1CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC3CC3)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 μmol, 2.1 eq.), 18-crown-6 (30 mg, 113 μmol, 2.1 eq.) and 1-(bromomethyl)cyclopropane (15.3 mg, 113 μmol, 2.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (22 mg, 66% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 2-dimethylamino ethanol (27.1 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 132 as an off-white solid in 45.9% yield. LCMS m/z (%)=450 (M+H 35Cl, 100), 452 (M+H 37Cl, 32). 1H NMR (400 MHz. DMSO-d6) δ: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.95 Hz, 1H), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, J=9.04 Hz, 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, 3H), 2.55-2.51 (m, 2H), 2.10 (s, 6H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][C@H:6]([CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[CH2:5][O:4]2)[CH2:2]1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:12][CH2:11][C@@H:10]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:9][C@H:6]2[CH2:7][CH2:8][C:3]3([CH2:2][CH2:1]3)[O:4][CH2:5]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCC2(CC2)OC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCC3(CC3)OC2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The tert-butyl (S)-1-((R)-4-oxaspiro[2.5]oct-6-yl)-3-hydroxypropan-2-ylcarbamate (1.70 g, 5.92 mmol) and tosyl chloride (4.5 g, 23.7 mmol, 4.0 equiv) were dissolved in pyridine (30 mL) and the mixture stirred at room temperature for 17 hr. The pyridine was removed in vacuo and the residue partitioned between EtOAc and 1.0 M HCl. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The (S)-2-(tert-butoxycarbonylamino)-3-((R)-4-oxaspiro[2.5]oct-6-yl)propyl 4-methylbenzenesulfonate was purified by flash chromatography on silica eluting with 0-29% EtOAc in hexanes. The fractions were evaporated and used directly in the next step. MS ESI +ve m/z 464 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][NH2:6]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)cc(Br)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
Step G4. A mixture of 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 14.6 mmol) and hydrazine monohydrate (0.8 g, 16 mmol) in ethanol (150 mL) was refluxed for 4 hours. Upon cooling to room temperature, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 1H NMR (DMSO-d6) showed that the white solid is a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione. This material was used in subsequent steps without further purification.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[S:24]([CH3:27])(=[O:26])=[O:25])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Reaction time: 1 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in pyridine (1.19 ml) containing mesyl chloride (12 μl). The solution was stirred for 1 hour in a dry ice-carbon tetrachloride bath under nitrogen atmosphere. The solution was evaporated in vacuo and the residue was subject to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 4-formyl-6,9-dihydroxy-11-mesyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Cl[CH2:30][C:31]([N:33]1[CH2:42][CH2:41][C:36]2([O:40][CH2:39][CH2:38][O:37]2)[CH2:35][CH2:34]1)=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:30][C:31]([N:33]3[CH2:34][CH2:35][C:36]4([O:40][CH2:39][CH2:38][O:37]4)[CH2:41][CH2:42]3)=[O:32])[N:9]=2)[CH:7]=1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (32.0 g, 79.1 mmol) in DMF (400 mL) was treated with 2-chloro-1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-ethanone (20.8 g, 94.9 mmol) and Cs2CO3 (51.5 g, 158.1 mmol) and the mixture was stirred at room temperature for 19 hours. The reaction was diluted with water (˜1.6 L) and the resultant precipitate was collected by filtration. The solid was washed with water dried under reduced pressure to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide as a beige solid (33.3 g, 72%). LCMS (Method 3) [M+H]+=588.2, RT=3.02 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6, 6.9 Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.8, 4.0 Hz), 8.42 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.30-7.26 (m, 1H), 7.00 (dd, 1H, J=4.2, 6.9 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.06 (s, 2H), 4.00-3.95 (m, 4H), 3.74 (dd, 2H, J=5.8, 5.8 Hz), 3.61 (dd, 2H, J=5.8, 5.8 Hz), 1.74-1.64 (m, 4H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)SC)([O-:3])=[O:2].[CH3:15][CH:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[N+:1]([CH:4]=[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:21][CH:16]([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2]
Reactant: CC(N)C(C)(C)C
Reactant: CSC(=C[N+](=O)[O-])Nc1ccccc1
Product: CC(NC(=C[N+](=O)[O-])Nc1ccccc1)C(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of 10.5 g (0.05 mol) of 2-nitro-1-anilino-1-methylthioethene and 15.2 g (0.15 mol) of 1,2,2-trimethylpropylamine was heated at 100° C. for 5 hours. After the mixture had cooled, it was concentrated on a rotary evaporator and the residue was recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])[O:9][C:3]=2[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: Nc1ccc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(Br)cc3o2)c(F)c1
Temperature: 195 °C
Yield: 13.2 %

Procedure:
2-amino-5-bromophenol (1.72 g, 9.2 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) were dissolved in polyposphoric acid (30 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Solid that formed was filtered and dried to obtain the crude. Crude was purified by combiflash using a gradient mixture of EtOAc and Petether (1:3) as eluent to afford the titled compound (450 mg) as a dark brown solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:22])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][CH2:24][CH:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]1>C1(C)C=CC=CC=1>[CH3:30][C:27]1([CH3:31])[O:26][CH:25]([CH2:24][O:23][C:9]([C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:11])=[O:22])=[O:10])[CH2:29][O:28]1
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Reactant: CC1(C)OCC(CO)O1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COC(=O)[C@H](Cc2ccccc2)C[C@@H](Cc2ccccc2)C(=O)O)O1

Procedure:
A solution of 1.0 g of (S,S)-2,4-dibenzylglutaric anhydride and 0.54 g of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane in 10 ml of toluene is refluxed overnight. The solution is washed with water, dried (Na2SO4), filtered and concentrated to give 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl]-(S,S)-2,4-dibenzylbutyric acid as a viscous oil.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].O>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
In 20 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution was added 2.08 g (10 mmol) of phosphorus pentachloride. The resulting mixture was stirred at room temperature for 1 hour. After the completion of the reaction, thereto was added 20 ml of chloroform and the resulting mixture was poured into 50 ml of iced water to separate an organic layer. The organic layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and dried over 4 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.03 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.33 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][N:27]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[N:13]([CH2:33][CH2:32][C:29]4[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][CH:30]=4)[C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(C(F)(F)F)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl.Cl.[F:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.Br[CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH:4]([F:3])[CH2:5]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: FC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCN1CCC(F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 3-Fluoro-pyrrolidine dihydrochloride salt (448 mg, 3.584 mmol) in anhydrous acetonitrile (24 mL) was treated with bromopropoxy-tert-butyldimethyl silane (0.83 mL) and then with K2CO3 (2.5 g, 5 equiv.). The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was subsequently diluted with water (75 mL) and extracted with a 6:1 mixture of Hexane and diethyl ether (2×100 mL). The organic layer was washed with NaHCO3(aq) (100 mL) and brine (100 mL) then dried over anhydrous K2CO3. Following filtration and concentration of the filtrate in vacuo the crude product was purified by flash silica gel chromatography (MeOH:EtOAc, 1:20). By 1H NMR the resulting clear oil (0.8 g) was the desired 1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-3-fluoro-pyrrolidine in a 10:1 ratio with the t-butyldimethylsilanol by-product. This residue was carried on without further purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: Cc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-(adamantan-1-yl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.02 (m, 2H), 7.73-7.76 (m, 1H), 7.47-7.50 (m, 2H), 7.37-7.40 (m, 2H), 2.42 (s, 3H), 2.05 (s, 2H), 1.94-1.99 (m, 3H), 1.65-1.73 (m, 9H), 1.57-1.64 (m, 3H); MS (APCI+) M/Z 428 (M+H)+.