Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:20][N:19]=4)[CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:44][N:45]1[CH:49]=[C:48]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]5[N:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][O:30][CH2:31][CH2:32]6)=[CH:22][N:23]=5)[CH:13]=4)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:47]=[N:46]1
Reactant: Brc1cnc2nnn(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(OCCN6CCOCC6)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
Under an argon atmosphere, 225 mg (0.24 mmol) of 6-bromo-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-1,2,3-triazolo[4,5-b]pyrazine are dissolved in 5 ml of ethylene glycol dimethyl ether, and 102 mg (0.48 mmol) of tripotassium phosphate trihydrate and 55 mg (0.26 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole are added. The reaction mixture is evacuated and flushed with argon twice. 14 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, the mixture is again evacuated and flushed argon. The reaction mixture is stirred at 80° C. for 16 hours. 10 ml of water are added to the reaction mixture, during which an oil precipitates out. This is extracted with dichloromethane and with dichloromethane comprising about 10% of MeOH, the aqueous phase is adjusted to pH 14 using 32% NaOH and again extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and purified by means of preparative HPLC, giving 42 mg of 6-(1-methyl-1H-pyrazol-4-yl)-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-1,2,3-triazolo[4,5-b]-pyrazine (“A2”); the product is in the form of the TFA salt; Rt.=2.26 (method A), LCMS: 499 (M+H);
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CN(C)C=O.CO>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Methyl isocyanate (0.18 g) was added to a stirred solution of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.57 g) in dimethylformamide (10 ml) and the mixture was stirred at room temperature for 3 hours and then diluted with methanol (2 ml). The solid was filtered off and crystallised from methanol to give the title compound, (0.32 g), m.p. 222°-224°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][N:29]2[CH3:34])#[N:2].C([O-])([O-])=[O:36].[K+].[K+].OO.O>CS(C)=O.CCOC(C)=O>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:36])=[C:4]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][N:29]3[CH3:34])[CH:5]=1
Reactant: Cn1ccc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ccc3C#N)cccc21
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cn1ccc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4N)ccc3C(N)=O)cccc21
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(4-cyano-3-(1-methyl-1H-indol-4-ylamino)phenylamino)cyclohexylcarbamate (90 mg, 0.19 mmol) in DMSO (2 mL). K2CO3 (130 mg, 0.94 mmol) and H2O2 (50% aq., 0.500 mL) were added. The mixture was stirred at 100 C for 10 min. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in TFA (2 mL). After 10 min of standing, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (10 mg). MS 378.3 (M+H); UV 224.7, 291.5 nm
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:8]3[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=3[C:1]#[N:2])=[CH:29][CH:28]=2)=[O:34])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.32 g, 5.59 mmol), N-(4-chlorophenethyl)-4-hydroxybenzamide (1.85 g, 671 mmol), and potassium carbonate (0.93 g, 6.70 mmol) in DMSO (10 ml) was stirred at 90° C. for 1 day. The reaction was cooled, diluted with ethyl acetate, and washed with 10% aqueous Na2CO3. The aqueous layer was back extracted with ethyl acetate. The organic washes were combined, washed with 10% Na2CO3 and brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes gave tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 40%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([OH:15])=O)([O-:9])=[O:8].CN(C=O)C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])([O-:9])=[O:8]
Reactant: Nc1ccccc1
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Yield: 74 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid (4.00 g, 20.51 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (3.8 mL, 41.70 mmol) to afford the 5 product (4.1 g); m.p. 111-113° C. after trituration in hexane.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>C(O)C.O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 68.8 %

Procedure:
147 g of the crude diethyl 2-methyl-2-(4-nitrophenyl)-malonate was dissolved in 600 ml of ethanol, and to this was added a solution of 42.4 g (0.846 mole) of 93% sodium hydroxide in 400 ml of water and the solution was reacted at 50° C. for 3 hours. After that, to the reaction mixture was added 1 l of water and the formed oily substance and an aqueous layer were separated. The aqueous layer was acidified with conc. hydrochloric acid and was extracted with 700 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering out magnesium sulfate, ethyl acetate was distilled off to give 66.8 g of crude 2-(4-nitrophenyl)propionic acid.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:26][C:27](N)=[S:28].S1(CCCC1)(=O)=[O:31]>O>[CH3:25][C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]2[S:28][C:27](=[O:31])[NH:26][C:3]2=[O:5])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)(COc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3.6 g of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate, 0.73 g of thiourea and 3 ml of sulfolane is heated at 120° C. for 4 hours and after cooling, 15 ml of water is added. The oil is separated, ether is added to the oil and the crystalline insolubles (a) are separated from the solution (b) by filtration. The filtrate (b) is distilled to remove the solvent and the residue is run onto a column of 100 g silica gel, elution being carried out with chloroform. By the above procedure is obtained 1.7 g of 5-[4-(2-methyl-2-phenylpropyloxy)benzyl]thiazolidine-2,4-dione. m.p. 107°-108° C. (benzene-ligroin)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].I[CH:19]([CH3:21])[CH3:20].O>CC(C)=O>[CH:19]([O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([CH3:21])[CH3:20]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C#N)c(OC(C)C)c1
Yield: 87.4 %

Procedure:
Cesium carbonate (51.5 g, 158 mmol) was added to a solution of 2-hydroxy-4-methoxybenzonitrile (11.8 g, 79 mmol) in acetone (100 mL). 2-Iodopropane (12.5 mL, 125 mmol) was added. The mixture was heated at reflux for 3 h. Water was added and the mixture was extracted with diethyl ether (4×100 mL). The combined organic extracts were washed with diluted ammonium hydroxide, brine and dried (MgSO4). Evaporation of the solvents and chromatography of the residue over silica gel using 5% diethyl ether in hexanes gave 2-isopropoxy-4-methoxybenzonitrile (13.2 g, 87%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6]O)=[CH:2]1.C1(P([N:22]=[N+:23]=[N-:24])(C2C=CC=CC=2)=O)C=CC=CC=1.CCCCCCC=CCCC>C1(C)C=CC=CC=1>[N:22]([CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccoc1
Agent: CCCC=CCCCCCC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccoc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a 50 mL round-bottomed flask equipped with a magnetic stirbar was added 3-furan methanol (1.00 g, 10.2 mmol) and a solution of diphenyl phosphoryl azide (3.37 g, 12.2 mmol) in toluene (30 mL). The stirring solution is allowed to cool to 0° C., in which 1, 8 Diazabycyclo [5.4.0.]undec-7-ene (1.86 g, 12.2 mmol) was added dropwise. The reaction is allowed to slowly warm to ambient temperature for an additional 16 hours of stirring. After this period, the reaction mixture is washed with water (2×20 mL) and then with 5% HCl (20 mL). Volatiles are evaporated under reduced pressure. The resulting residue is then purified by column chromatography (1:9 ethyl acetate/hexane) providing 3-azidomethyl furan (1.19 g, 95%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H), δ 7.44 (s, 1H), δ 6.42 (d, 1H), δ 4.20 (s, 2H). ppm; 13C NMR (75 MHz, CDCl3) δ 144.1, 141.1, 110.4, 92.1, 45.8 ppm; LRMS (EI) calcd for C5H5N3O (M+) 123. found 123.
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][CH:6]1[CH2:11][S:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24].Cl>O.C1(C)C=CC=CC=1>[ClH:1].[CH2:21]([N:5]([CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:11][S:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: CCCNC1CSc2sccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN(CCC)C1CSc2sccc2C1

Procedure:
A mixture of 2,5 g of N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, 7.5 g of sodium carbonate, 11 ml of n-butyl iodide 25 ml of toluene and 25 ml of water is refluxed for 3 days. Removal of solvent from the organic layer affords an oil which is treated with ethanolic hydrochloric acid to afford N-butyl- N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, m.p. 161°-164°.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH2:45][C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:55])[CH2:52][C:53]#[N:54])[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][C:32]=3[F:44])[C:23]=12>C(Cl)Cl.CCOC(C)=O>[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH2:45][C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51]([C:52](=[CH:3][C:2]([CH3:5])([NH:6][CH:7]3[CH2:10][O:9][CH2:8]3)[CH3:1])[C:53]#[N:54])=[O:55])[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][C:32]=3[F:44])[C:23]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)NC1COC1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC1COC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
To a solution of 2-methyl-2-(oxetan-3-ylamino)propanal (106.3 mg, 0.7400 mmol) in DCM (5 mL) was added pyrrolidine (0.07 mL, 0.890 mmol). The reaction mixture was cooled to 0° C., followed by addition TMS-Cl (0.08 mL, 0.59 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 10 minutes before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (70 mg, 0.1500 mmol). The mixture was stirred for 50 minutes at which point it was deemed finished by checking TLC and LC-MS. The mixture was washed with saturated Na2HCO3 and the layers separated. The aq. layer was extracted with CH2Cl2, and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed. The residue was loaded on silica gel plate, flashed by [MeOH:CH2C2(1:4)]: EtOAc 50%, 60% to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(oxetan-3-ylamino)pent-2-enenitrile (35.6 mg, 0.0597 mmol, 40.2% yield) as an off white solid. LC-MS (ES, m/z): 598 [M+H].
Reaction SMILES: [CH3:1][S:2][C:3]([NH:5][NH2:6])=[S:4].[F:7][C:8]([F:30])([F:29])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1>CCO.O>[F:30][C:8]([F:7])([F:29])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:28]=[CH:27][C:24](/[CH:25]=[N:6]/[NH:5][C:3]([S:2][CH3:1])=[S:4])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CSC(=S)NN
Solvent: O
Solvent: CCO
Product: CSC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 80 °C

Procedure:
To a 250 mL round-bottom flask containing hydrazinecarbodithioic acid methyl ester (2.38 g, 1.95 mmol) in EtOH (100 mL) was added 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (5.00 g, 1.50 mmol). The vessel was heated at 80° C. for 3 h before being diluted with H2O (300 mL) and cooled to 0° C. The precipitated product was collected by vacuum filtration as an off-white solid (6.13 g, 93%) mp 204-206° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.43 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 2.57 (s, 3H); ESIMS m/z 438 (M+H).
Reaction SMILES: [C:1]([C@H:4]([N:9]([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([CH2:25]OS(C)(=O)=O)=[CH:23][CH:22]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].C[CH2:34][N:35](CC)[CH2:36]C.CNC>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:1]([NH2:2])=[O:3])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:35]([CH3:36])[CH3:34])=[CH:31][CH:32]=2)(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(COS(C)(=O)=O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: CNC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of methanesulfonic acid 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzyl ester (150 mg, 0.298 mmol) in (3 mL) CH2Cl2 at 0° C. was added 1 equivalent of Et3N, followed by dimethylamine (0.3 mL, 2 M in THF). The reaction was stirred overnight at rt. The mixture was diluted with CH2Cl2, washed with H2O, brine, dried over MgSO4, and concentrated to give an amber glass. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (95 mg) in 71% yield. MS (EST), (M+H)+ 452.23, 1H NMR (CDCl3) δ 7.94 (d, 2H, J=8.0), 7.74 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0) 7.38 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.35 (br s, 1H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.28-3.23 (m, 3H), 2.17 (br s, 6H), 1.95 (m, 1H), 1.55 (m, 2H), 0.96 (d, 3H, J=7.0), 0.93 (d, 3H, J=7.0).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][N:2]1[C:18](OC(C)(C)C)=O.C(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:18]([N:2]1[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:12]=3[C:13]=2[CH2:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C(=O)OC(C)(C)C)CC3
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 2-tert-butyl 8-methyl 3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (0.50 g, 1.5 mmol) in DCM (5.0 mL), TFA (5.0 mL) was added. After allowing the reaction mixture to stir at room temperature for 1 h, the volatiles were evaporated, DCM and toluene (20 mL) were added and the volatiles evaporated (2×). The resulting residue was dissolved in THF/MeOH (4:1, 10 mL) and benzaldehyde (0.17 mL, 0.18 g, 1.7 mmol) and sodium triacetoxyborohydride (0.485 g, 2.3 mmol) were added. The reaction mixture was allowed to stir at room temperature overnight and 4 more equivalents of the aldehyde and reducing agent were added to cause the reaction to go to completion. The reaction mixture was then poured into saturated sodium bicarbonate solution (300 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated to give a foamy residue. Column chromatography (DCM→3% MeOH/DCM) provided methyl 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (12a in Scheme 1(h)) as a white solid (0.32 g, 66%). 1H NMR (CD3OD, 300 MHz) 8.17 (d, J=1.1 Hz, 1H), 7.73 (dd, J=8.7, 1.8 Hz, 1H), 7.44-7.27 (m, 6H), 3.88 (s, 3H), 3.83 (s, 2H), 3.73 (s, 2H), 2.95-2.88 (m, 4H) ppm; MS (ES) 321 (M+H).
Reaction SMILES: C1(C(OC)[C:8]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:9]=2[CH2:10][NH:11][C:12]2[N:13]=[N:14][N:15]([CH3:17])[N:16]=2)CCCCC1.[H-].[Na+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36].CN([CH:47]=[O:48])C>>[CH2:8]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:9]1[CH:10]([CH:10]([N:11]([CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36])[C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1)[C:9]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][CH:8]=1)[O:48][CH3:47]
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(c1ccc(C(F)(F)F)cc1CNc1nnn(C)n1)C1CCCCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(C1CCCCC1)C(c1cccc(C(F)(F)F)c1)N(Cc1cc(C#N)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of [2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine (28 mg, 0.073 mmol) in DMF (2 mL) at 0° C. under nitrogen was added sodium hydride (4.4 mg, 0.11 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes, allowing it to warm to room temperature. The reaction mixture was then treated with 3-(bromomethyl)-5-(trifluoromethyl)benzonitrile (19.3 mg, 0.073 mmol) at room temperature and stirred for overnight. Solvent was removed in vacuo. The residue was diluted with ethyl acetate and washed with satd. sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulphate and concentrated in vacuo. The product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1CV), 2-20% (10CV), 20% (2CV) to yield the title compound (21 mg, 49%) as a colorless oil, 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (m, 4H) 1.2 (m, 3H) 1.65(m, 3H) 1.73 (m, 1H) 3.18 (s, 3H) 4.06 (s, 3H) 4.2 (m, 1H) 4.67-5.04 (m, 2H) 5.4 (m, 1H) 7.39 (s, 1H) 7.50 (m, 3H) 7.5 (m, 2H). MS (ES+) Calc: 566.2, Found: 567.5 (M+1). According to the procedures described in Examples 42-45 and using the appropriate amine, Examples 46-50 were prepared.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([N:14]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccc(F)cc2)nc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Yield: 47 %

Procedure:
In an analogous manner to that described in Example 36c), the reaction of 6-(4-fluoro-benzyloxy)-pyridin-3-ylamine with itaconic acid yields the crude (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid as a green solid (yield 47% of theory).
Reaction SMILES: [O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Br[CH2:37][CH2:38][CH2:39][OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:37][CH2:38][CH2:39][OH:40])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1c(OCCCO)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of trans-2-[3-(2-oxopropylsulfonyl)-4-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (30 mg, 0.059 mmol), 3-bromo-1-propanol (12 uL, 0.13 mmol) and potassium carbonate (17 mg, 0.12 mmol) in DMF (0.5 mL) was heated at 80° C. with stirring under nitrogen for 1 h. The reaction mixture was cooled and diluted with ethyl ether. It was washed with water (2 x), brine, dried, filtered, and evaporated to a residue, which was purified by preparative TLC (hexane-ethyl acetate; 7:3, v/v) to give the title compound: Rf 0.3; NMR (CDCl3) δ 2.38 (s, SO2CH2COCH3), 4.15 and 4.24 (2 t, OCH2CH2), 4.48 (s, SO2CH2), 5.22 (m, H-2 and H-5).