Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:14]([CH2:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])[O:13][C:12]1([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C@H:14]([CH2:23][C@@H:24]([CH:28]([CH3:29])[CH3:30])[C:25]([NH:37][CH2:33][CH2:34][CH2:35][CH3:36])=[O:26])[O:13][C:12]1([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: CC(C)C(C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1)C(C)C
Reaction time: 8 h

Procedure:
The crude carboxylic acid (I) (551 mg) was dissolved in DMF (10 ml) containing triethylamine (126 mg). Butylamine (109 mg), HOBT (169 mg) and EDAC (240 mg) were added and the solution was allowed to stand overnight. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated and washed with saturated sodium hydrogen carbonate solution (20 ml), followed by water (20 ml) and then saturated sodium chloride solution (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4 v/v), to give initially (2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide (J), as a clear oil (103 mg); NMR (CDCl3): 0.9 (m, 9H), 1.0-2.1 (complex m, 27H), 3.25 (q, 2H), 3.75 (m, 2H), 5.1 (dd, 2H), 5.6 (br, 1H), 7.3 (m, 5H); and then the corresponding (2R)-isomer, as a clear oil (133 mg); NMR (CDCl3): 0.9 (m, 9H), 1.0-2.1 (complex m, 27H), 3.25 (m, 2H), 3.75 (m, 1H), 3.9 (m, 1H), 5.1 (dd, 2H), 5.4 (br, 1H), 7.4 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]=[C:30]=[O:31])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=NCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-(3-trifluoromethylphenyl)ethylamine (5.65 mmol) at 0° C. was added solid Proton sponge (5.65 mmol) then a 20% solution of phosgene in toluene (5.65 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (m, 4H); 3.6 ppm (t, 2H); 2.95 ppm (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:22]2[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:27]=2)[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.Cl.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>O1CCOCC1.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1C1=CCNCC1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Into a microwave vial was added tert-butyl 4-{3-chloro-2-fluoro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (10.5 mg, 0.021 mmol) and 4.0 M HCl in 1,4-dioxane (1.0 mL). The mixture was stirred for 30 min and evaporated. Methylene chloride (1.0 mL) and DIPEA (15.6 μL, 0.090 mmol) were added followed by methanesulfonyl chloride (4.8 pt, 0.063 mmol). The mixture was stirred for 15 minutes. The solvents were evaporated. 1 N sodium hydroxide solution (1.0 mL) and methanol (1.0 mL) were added and the mixture was stirred for 1 hour. The solvents were evaporated and purification by preparative LC/MS (pH 10) gave the desired compound (4.0 mg, 40%). LCMS calculated for C20H23ClFN6O3S (M+H)+: m/z=481.1. found: 481.0. 1H NMR (DMSO-d6, 500 MHz) δ 12.88 (1H, br s), 8.18 (2H, m), 7.63 (1H, m), 5.91 (1H, m), 5.78 (1H, br s), 3.94 (5H, m), 3.40 (2H, m), 2.98 (3H, s), 2.55 (2H, m), 2.39 (2H, m), 1.42 (3H, m).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Cl.Cl[CH:12]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21])[C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][C:12]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=1
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)c1ccccn1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc(N)sc1C(=O)c1ccccn1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of thiourea (4.5 g) and sodium acetate (5 g) in a mixture of tetrahydrofuran (50 ml) and water (15 ml) was added ethyl 3-chloro-4-(2-pyridyl)-2,4-dioxo-butyrate hydrochloride (5.6 g). After the mixture was stirred at 45° C. to 50° C. for 2 hours, water (50 ml) was added thereto. The resulting mixture was acidified to pH 1.0 with 10% hydrochloric acid. The precipitate was collected by filtration. The precipitate was added to a mixture of water and ethyl acetate, and adjusted to pH 6.0 with 10% potassium carbonate. The separated ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give ethyl 2-amino-5-(2-pyridinecarbonyl)-4-thiazolecarboxylate (1.1 g).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1.[Cl-:18].[NH4+:19]>>[ClH:18].[C:12]1([CH:11]=[CH:10][CH2:9][CH:7]2[NH:8][C:3](=[NH:19])[CH2:4][CH2:5][CH2:6]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Cl-]
Reactant: COC1=NC(CC=Cc2ccccc2)CCC1
Reactant: [NH4+]
Product: Cl
Product: N=C1CCCC(CC=Cc2ccccc2)N1

Procedure:
The product of Example 97 is reacted with ammonium chloride by the method of Example 5 to generate tee compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@H:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1N
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-ylamine (0.73 g, 2.74 mmol) in THF (15 ml) was added a solution of K2CO3 (0.75 mg, 5.48 mmol) in H2O (5 ml). After 10 minutes, ethyl chloroformate (0.27 ml, 2.87 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (11 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (60 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.27 g (35%) of rac-((3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-yl)-methyl-amine as a colorless oil. ES-MS m/e: 281.3 (M+H+).
Reaction SMILES: Br[C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[OH:22].O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:32])C=1Cl.CCCCCC>C1COCC1>[OH:32][C:2]1[C:3](=[O:22])[C:4]([O:20][CH3:21])=[CH:5][C:6]2[C:15]=1[S:14](=[O:17])(=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[CH:12]=1)[N:7]=2
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC1=CC2=Nc3ccc(OC)cc3S(=O)(=O)C2=C(O)C1=O
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 4-bromo-3-hydroxy-2,7-dimethoxy-10H-phenothiazine-5,5-dioxide (100 mg) in THF (10 ml) was added water (0.1 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.12 g). After 20 minutes, hexane was added and the solid was filtered, washed with ether and air dried to afford the title compound, m.p. 333°-335° C. (dec.)
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][NH:13][CH2:14]2)[CH2:10][CH2:9]1)=[O:6].C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>ClCCl>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][N:13]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=3)(=[O:40])=[O:39])[CH2:14]2)[CH2:10][CH2:9]1)=[O:6]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-4-methyl-2-morpholino-N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)pentanamide (191 mg, 0.617 mmol), triethylamine (0.129 mL, 0.926 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.109 mL, 0.679 mmol) were combined in dichloromethane (0.5 mL). The reaction was stirred at room temperature for 3 hours. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=6.2, 1H), 8.38 (s, 1H), 8.19 (d, J=7.9, 1H), 7.92 (d, J=7.8, 1H), 7.72 (t, J=7.9, 1H), 4.27-4.20 (m, 1H), 3.90 (dd, J=2.3, 10.0, 1H), 3.76-3.67 (m, 4H), 3.20 (ddd, J=3.9, 9.4, 10.9, 3H), 2.97 (dd, J=7.1, 9.6, 1H), 2.78-2.72 (m, 2H), 2.72-2.67 (m, 2H), 2.62-2.53 (m, 2H), 1.94 (dt, J=6.2, 12.1, 1H), 1.89-1.77 (m, 3H), 1.64-1.54 (m, 2H), 1.30 (ddt, J=6.5, 9.3, 12.8, 1H), 0.92 (d, J=4.4, 3H), 0.91 (d, J=4.4, 3H); MS (ESI+) m/z 518 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[CH2:28]([NH:35][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CNCc2ccccc2)CC1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (52 mg, 0.143 mmol) was dissolved in THF (2 mL) and benzylamine (0.025 mL, 0.285 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (18 mg, 0.285 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 23 mg, 0.050 mmol, 40%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37-7.23, 7.14, 7.12-7.02, 6.89, 6.59, 5.46, 4.62, 4.09, 3.76, 2.75, 2.44, 1.98-0.49
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][N:9]([C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:8]2)=O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Si:14]([O:13][CH2:12][C@@H:11]1[CH2:10][N:9]([C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:8][C@@H:7]1[CH2:5][NH:4][CH:1]1[CH2:2][CH2:3]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](C(=O)NC2CC2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](CNC2CC2)C1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
(3R,4S)-N-Cyclopropyl-4-(tert-butyldimethylsilyl)oxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (7.00 g) was dissolved in toluene (70 mL). To this solution, borane-dimethyl sulfide complex (2.20 mL) was added and the mixture was heat-refluxed for 5 hours while being stirred. Subsequently, the reaction mixture was allowed to cool to room temperature. Following addition of a 10% aqueous solution of sodium carbonate (42 mL), the mixture was stirred at 100° C. for 1 hour and the toluene layer was separated. The toluene layer was washed with water (2×30 mL), was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=4:1) to give 4.78 g of (3S,4S)-4-(tert-butyldimethylsilyl)oxymethyl-3-cyclopropylaminomethyl-1-[(1S)-1-phenylethyl]pyrrolidine as a colorless oil.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[N:9][C:10]=1[O:11][CH2:12][CH:13]([F:15])[F:14]>CO>[ClH:4].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:16][NH2:17])[CH:8]=[N:9][C:10]=1[O:11][CH2:12][CH:13]([F:14])[F:15]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)F)c(Cl)c1
Agent: NN
Solvent: O
Solvent: CO
Product: Cl
Product: NCc1cnc(OCC(F)F)c(Cl)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 182.3 %

Procedure:
Hydrazine monohydrate (0.53 mL, 10.8 mmol) is added to a solution of 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.27 g, 3.60 mmol, Step-4) in methanol (50 mL) and stirred for 20 hours at 50° C. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3). The organic layer is dried over sodium sulfate. After filtration, the organic layer is concentrated in vacuo. The residue is dissolved in EtOAc (10 mL), 4 M hydrogen chloride in EtOAc (5 mL) is added and stirred for 1 hour. After removal of the solvent, the residue is crystallized from EtOAc/n-hexane to give 0.85 g (91% yield) of the title compound as white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][Cl:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[CH:30]=[N:29][N:28]=[C:27]1[SH:31].[I-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[ClH:20].[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:31][C:27]3[N:26]([CH3:25])[CH:30]=[N:29][N:28]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1
Reactant: Cn1cnnc1S
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cl
Product: Cn1cnnc1SCCCN1CCN(c2cc(C(C)(C)C)nc(C(C)(C)C)n2)CC1
Yield: 83 %

Procedure:
1 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-pyrimidine (2.83 mmol), 0.35 g of 4-Methyl-4H-[1,2,4]triazole-3-thiol (3.04 mmol), 0.2 g of lithium-hydroxide (8.35 mmol) and a spatula tip of potassium iodide werde stirred for 72 h in 20 ml of dimethylformamide. Water and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The resdue was subjected to a column chromatography on silica gel using dichloromethane-methanol(2-10%). Fractions containing the product were combined, the solvent was evaporated and the residue re-dissolved in isopropanol. The solution was treated with HCl/isopropanol. Diisopropylethylether was added whereby an oily precipitate formed. The solvent was decanted and the remaining oil evaporated to dryness to yield 1.1 g (77%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([OH:26])=O)C=C[N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[N:34][NH:35]2.[CH3:40][N:41](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH:35]1[C:36]2[C:32](=[C:31]([NH:30][C:24]([C:22]3[CH:23]=[C:18]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:29]=[CH:28][C:6]=6[NH:7][C:8]5=[O:27])[CH2:13][CH2:14]4)[N:19]=[CH:40][N:41]=3)=[O:26])[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: Nc1cccc2[nH]ncc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)Nc4cccc5[nH]ncc45)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 34 mg (0.25 mmol) 4-amino-indazole in 74 mμL (0.53 mmol) TEA and 1.5 mL DMF were combined with 89 mg (0.28 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]=2[N+:14]([O-:16])=[O:15])=[CH:28][CH:27]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: Fc1ccc(CBr)cc1
Product: COC(=O)Cn1c(C)cc(Cc2ccc(F)cc2)c([N+](=O)[O-])c1=O

Procedure:
This compound is prepared from 11 g (29.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 10 g (52.9 mmol) of (4-fluorophenyl)-methyl bromide according to the method described in 1.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:28].S(Cl)([Cl:32])(=O)=O.O>C(Cl)Cl>[Cl:32][C:4]1[CH:5]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:25])([F:26])[F:27])[CH:9]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:28]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)cc(Cl)c1O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol (0.332 g, 0.8. mmol) in CH2Cl2 (10 ml) was added sulfuryl chloride (0.113 g, 0.84 mmol) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with CH2Cl2-hexane to give the subtitle compound (0.318 g, 88.6% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][NH:6][CH2:5][C:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:3]1=2.CCN(C(C)C)C(C)C.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[CH2:7][N:6]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N+:26]([O-:28])=[O:27])(=[O:36])=[O:37])[CH2:5][C:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:3]1=2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2c(s1)C(C)(C)CNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(s1)C(C)(C)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A solution of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20.5 g, 0.074 mol) and DIPEA (42.8 g, 0.37 mol) in DCM (400 mL) was cooled to 0° C. 2-nitrobenzene-1-sulfonyl chloride (17.3 g, 0.078 mol) was then added and the reaction mixture was allowed to warm to room temperature overnight. The crude reaction solution was applied directly to a silica gel column and purified (10-20% EtOAc/hexane) to afford product (27.6 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J=4.8, 2.4 Hz, 1H), 7.64-7.68 (m, 2H), 7.57 (dd, J=4.4, 2.4 Hz, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 4.33 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.33 (s, 2H), 1.31 (s, 6H), 1.19 (t, J=7.2 Hz, 3H),
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:26](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:27][C:28]1([CH3:31])[CH2:30][CH2:29]1>>[CH3:31][C:28]1([O:27][C:26]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH:19]=3)[CH2:21][CH2:22]2)=[O:32])[CH2:30][CH2:29]1
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Product: CC1(OC(=O)N2CCC(c3cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4o3)CC2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and 1-methyl-cyclopropyl 4-nitrophenyl carbonate following a procedure analogous to that described for Example 20. Mass spectrum (ESI+): m/z=460 [M+H]+.