Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]([O:24][CH2:25]C)=[O:23].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][C:15]5[C:20]([CH:21]=4)=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:10]=3)[N:5]=[CH:4][C:3]=2[C:22]([O:24][CH3:25])=[O:23])[CH2:33][CH2:32]1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of ethyl 4-chloro-6-quinolin-3-yl-1,5-naphthyridine-3-carboxylate (compound 41) (6.0 g, 17 mmol), 4-amino-1-N-Cbz-piperidine (compound 45) (4.1 g, 17 mmol), and potassium carbonate (4.6 g, 33 mmol) in N,N-dimethylacetamide (100 mL) was heated to 90° C. After 2 hours, the reaction was cooled to room temperature and filtered. The filtrate was concentrated and the residue was triturated with methanol to afford methyl 4-({1-[(benzyloxy)carbonyl]piperidin-4-yl}amino)-6-quinolin-3-yl-1,5-naphthyridine-3-carboxylate (compound 46) as a cream solid (8.2 g, 90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:11]=1.C[CH2:38][O:39]CC>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22](=[NH:23])[O:39][CH3:38])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[CH:11]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C#N)c3)cc12
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=N)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1

Procedure:
HCl gas was bubbled through a suspension of 3-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzonitrile (287.8 mg, 0.60 mmol) in 3.5 mL of anhydrous MeOH. The mixture was then stirred for 5 hours at room temperature before ether (20 mL) was added. The precipitate was then collected by filtration and dried to afford methyl 3-(3-(2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzimidate without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: FC(F)(F)c1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, light brown solid (37 mg, 29%), MS (ISP) m/z=439.4 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-trifluoromethyl-phenyl)-1H-benzo[d]imidazole (intermediate I) (100 mg, 293 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (71.7 mg, 322 μmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:5]([O:8][CH3:13])=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1OC(F)F
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)cc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in step 3(a)-v of Scheme 3(a), 5-bromo-3-(difluoromethoxy)pyridin-2-ol (300 mg; 1.25 mmol) was dissolved in 5 mL of chloroform. Silver carbonate (690 mg; 2.5 mmol) and methyl iodide (780 μL; 1.77 g; 12.5 mmol) were added and the mixture stirred at RT overnight. The reaction mixture was filtered through diatomaceous earth, which was washed with additional CHCl3. The filtrates were concentrated under reduced pressure to yield an oil which was purified by silica gel chromatography to yield 5-bromo-3-(difluoromethoxy)-2-methoxypyridine as a white solid (Compound 2010, 250 mg, 78% yield): ESMS (M+H) 254/256; 1H NMR (CDCl3) δ 8.08 (d, 1H, J=2.1 Hz), 7.56 (d, 1H, J=2.1 Hz), 6.60 (t, 1H, J=75 Hz), 3.98 (s, 3H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:21][C:22](=[O:45])[NH:23][CH:24]([C:29](=[O:44])[NH:30][CH:31]([C:41](=O)[NH2:42])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>O1CCCC1>[CH2:14]([O:21][C:22](=[O:45])[NH:23][CH:24]([C:29](=[O:44])[NH:30][CH:31]([C:41]#[N:42])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:25][CH:26]([CH3:27])[CH3:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(COCc1ccccc1)C(N)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(C#N)COCc1ccccc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
0.3 ml of trifluoroacetic acid anhydride is added dropwise to a solution of 0.9 g of [1-(2-benzyloxy-1-carbamoyl-ethylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester and 0.6 ml of triethylamine in 15 ml of tetrahydrofuran at −5° C. The reaction mixture is stirred at −5° C. for 3 hours and then for 12 hours at room temperature. The reaction mixture is then poured into H2O and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed once with H2O and once with brine, then dried over sodium sulfate, the solvent is removed and the residue is crystallized from diethylether/hexane. Mp.: 126-127° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:15]C(C)([O-])C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccc(S(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
In a round-bottomed flask, 3-iodo-6-methylsulfonyl-1H-indazole (396 mg, 1.23 mmol) was dissolved in THF (4.4 ml). The orange solution was cooled to 0° C. and potassium tert-butoxide (200 mg, 1.78 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.11 ml, 1.76 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient: 0-30% EtOAc) to give 251 mg (61%) of 3-iodo-6-methanesulfonyl-1-methyl-1H-indazole as an off-white solid. The minor regioisomer 3-iodo-6-methanesulfonyl-2-methyl-2H-indazole was also observed, but not isolated.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:16][C:17]([CH2:19][CH2:20][CH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:18])[C@H:9]([C:11]([O:13]CC)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CC(O)=O>[CH2:1]([C@@H:8]([NH:16][C:17]([CH2:19][CH2:20][CH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:18])[C@H:9]([C:11]([OH:13])=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)CCCc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(CCCc1ccccc1C(=O)O)N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reaction time: 4 h
Yield: 95 %

Procedure:
Two thirds of the crude 2-[3-((1R,2R)-1-benzyl-2-ethoxycarbonyl-2-hydroxy-ethylcarbamoyl)-propyl]-benzoic acid for the previous example, was combined with THF (8 mL) and 10 M aqueous NaOH (134 μL, 4.0 eq.). The reaction was stirred for 4 hours. Upon completion of the reaction was completed, AcOH (1.5 mL) was added and the product was purified by preparative HPLC to yield the title compound (50 mg, 95% purity). MS m/z [M+H]+ calc'd for C21H23NO6, 386.15. found 386.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([O:26]CC4C=CC=CC=4)=[CH:21][C:20]=3[O:34]CC3C=CC=CC=3)=[N:16][NH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([OH:26])=[CH:21][C:20]=3[OH:34])=[N:16][NH:17][CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2cc(Cl)c(O)cc2O)CC1
Yield: 45.6 %

Procedure:
A solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (230 mg, 0.4 mmol) in ethyl acetate (15 ml) was hydrogenated over 10% palladium on carbon for 1.5 h. The suspension was filtered through celite, washing with dichloromethane:ethanol (1:1). The filtrate was concentrated to leave 4-[3-(5-chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (Example 1) as a white solid (72 mg)
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=C(F)C=4)=C(Cl)C=2)=NC=N3)CC1.C(O)(C(F)(F)F)=O>CO>[Cl:35][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[C:18]3=[C:10]([CH2:9][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:11]=[CH:12][N:13]3[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Reactant: C1CNCCN1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(COc2ccc(Nc3ncnn4ccc(CN5CCNCC5)c34)cc2Cl)c1

Procedure:
The title compound was prepared from 7B and excess piperazine by a route analogous to that used for the preparation of 7C. Analytical HPLC retention time=1.68 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=467.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N+]=[N-])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:1]([O:11][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a solution of 25.0 g (164 mmol) of D-mandelic acid in 200 ml of ethyl acetate was added 38.9 g (164 mmol) of diphenyldiazomethane under stirring at room temperature. The completeness of reaction was monitored by TLC and the reaction mixture was concentrated. The residue was recrystallized from etherpetroleum ether to give 47.7 g of the aimed product D-5 in 91% yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[F:7][C:8]([F:16])([F:15])[C:9]([CH2:11][C:12](=O)[CH3:13])=O.C([O-])([O-])=O.[K+].[K+]>O>[CH3:13][C:12]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:9]([C:8]([F:16])([F:15])[F:7])[CH:11]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: N#CCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C(F)(F)F)c(C#N)c(=O)[nH]1
Temperature: 23 °C
Reaction time: 15 h
Yield: 52.5 %

Procedure:
To a solution of 2-cyanoacetamide (14.0 g, 166 mmol) and trifluoroacetylacetone (20.0 ml, 166 mmol) in H2O (332 ml) was added K2CO3 (6.60 g, 47.9 mmol). The mixture was stirred at 23° C. for 15 h. The precipitated solid was filtered with Buchner funnel, washed with ice cold H2O, and dried with hot air (60° C., 16 h) to give the titled compound (17.6 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.38 (s, 3H), 6.66 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6])C.CO>[OH-].[Na+]>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[C:4]([OH:15])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C(=O)O)cc1
Temperature: 80 °C

Procedure:
4-Methoxyphenylglyoxylic ethyl ester obtained in Example 20 was dissolved in 20% sodium hydroxide (60 mg) and methanol (600 ml) and then stirred for 3 hours with heating at 80° C. When the reaction is completed, the reaction solution was extracted with diethyl ether (200 mg) and the obtained aqueous solution was acidified (pH 1-2) with hydrochloric acid. The resulting aqueous acidic solution was extracted with dichloromethane, and the extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove the organic solvent to obtain 34.63 g (yield in two reaction steps: 43%) of the title compound as a pale violet solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5](O)=[O:6].[CH3:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=O)=[CH:30][N:29]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[O:6][C:5]([CH2:4][CH:3]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH:11]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=4)[CH2:10]3)[C:2]([F:26])([F:1])[F:25])=[N:35][N:34]=2)=[CH:30][N:29]=1
Reactant: Cc1ccc(C(=O)NN)cn1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nnc(CC(CN3CCCC(c4cccc(C(F)(F)F)c4)C3)C(F)(F)F)o2)cn1
Temperature: 110 °C
Yield: 15.3 %

Procedure:
To a round-bottomed flask (5 ml) was added 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanoic acid (60 mg, 157 μmol), 6-methylnicotinohydrazide (23.7 mg, 157 μmol) and POCl3 (1.64 g, 1 mL, 10.7 mmol). The reaction mixture was heated to reflux at 110° C. for 4 hr. The crude reaction mixture was allowed to cool to room temperature, poured into ice/water and made basic with a saturated solution of Na2CO3. The reaction mixture was extracted with ethyl acetate, washed with brine and H2O, dried over MgSO4, filtered and concentrated. The resultant residue was purified on a silica column (100% hexane to 60% ethyl acetate/hexane gradient) to afford 12 mg (15%) of 2-methyl-5-(5-{3,3,3-trifluoro-2-[3-(3-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-propyl}-[1,3,4]oxadiazol-2-yl)-pyridine as an off-white solid. MH+=499.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N[C@@H](Cc2cccnc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.82 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.61 g of the compound obtained in Step 85-2 as starting materials, 246 mg (Isomer A, yellow amorphous) and 536 mg (Isomer B, pale yellow amorphous) of the respective diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:13](=[O:17])[C@H:14]([OH:16])[CH2:15][C:4]=2[CH:3]=1.C1COCC1.[H-].[Na+].[O:30]=[C:31]1[C:40]([CH:41]2[CH2:46][CH2:45][N:44]([C:47](OC3C=CC([N+]([O-])=O)=CC=3)=[O:48])[CH2:43][CH2:42]2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1>>[O:30]=[C:31]1[C:40]([CH:41]2[CH2:42][CH2:43][N:44]([C:47]([O:16][C@H:14]3[C:13](=[O:17])[N:12]([CH2:18][C:19]([F:21])([F:20])[F:22])[CH2:11][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[C:2]([Cl:1])=[CH:3][C:4]=4[CH2:15]3)=[O:48])[CH2:45][CH2:46]2)=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1
Reactant: O=C1[C@H](O)Cc2cc(Cl)c3[nH]ncc3c2CN1CC(F)(F)F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reaction time: 48 h
Yield: 36.1 %

Procedure:
(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (60.0 mg, 0.180 mmol) in THF (10.0 mL, 122 mmol) was added sodium hydride (10.79 mg, 0.450 mmol) followed by 4-nitrophenyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (106 mg, 0.270 mmol). After stirring for 48 h, most of the solvent was removed, diluted with dichloromethane (30 mL) and neutralized with 1.0 M HCl. The organic phase was separated, dried (Na2SO4) and the crude product was purified by flash chromatography using 5% MeOH in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (38.00 mg, 0.065 mmol, 36% yield). MS (ESI) 588 (M+H); Rf=2.73.
Reaction SMILES: [Li+].[H-].[Al].[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[CH:15][N+:16]([O-])=O)=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.O>[NH2:16][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([Cl:4])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])C=C1CCCN1Cc1ccc(Cl)cc1
Agent: [Al]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCCN1Cc1ccc(Cl)cc1
Yield: 80.3 %

Procedure:
500 ml of anhydrous tetrahydrofurane and 23.4 g (0.615 mol) of the double hydride lithium and aluminium are introduced into a reactor equipped with a mechanical stirrer, and a solution of 27.3 g (0.108 mol) of 1-p-chlorobenzyl-2-nitromethylene-pyrrolidine in 1,000 ml of tetrahydrofurane is then added slowly. The reaction mixture is heated at the reflux temperature for 12 hours and then cooled, and 53 ml of water are added dropwise, followed by 53 ml of 20% strength sodium hydroxide solution and finally 53 ml of water. The precipitate is filtered off and extracted with 500 ml of ether. The ether solution is combined with the filtrate and dried over magnesium sulphate, the solvents are evaporated and the residue is distilled under reduced pressure. 19.5 g (yield: 80.2%) of 2-aminomethyl-1-p-chlorobenzyl-pyrrolidine distilling at 118°-120° under a pressure of 0.06 mm of mercury are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH2:12][CH3:13])[CH:3]=1.OS(O)(=O)=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: CCc1cc(Cl)c(N)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCc1cc(Cl)cc([N+](=O)[O-])c1

Procedure:
To 6-chloro-4-ethyl-2-nitroaniline (5.3 g) in ethanol (40 ml) was added c.H2SO4 (5 ml) dropwise. The solution was heated to reflux and solid NANO2 (4.55 g) was added in small portions over 25 minutes. After a further 1 h at reflux the mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water (×3) and brine (×3), dried over MGSO4 and evaporated. 3-Chloro-5-ethylnitrobenzene was isolated as a yellow oil (4.0 g) after silica chromatography. δ (60 MHz, CDCl3) 1.2 (3H, t, CH3), 2.5 (2H, q, CH2), 7.5 (1H, s, Ar) and 7.9 (2H, s, Ar). This product was treated with iron powder (2.7 g) in acetic acid (40 ml) and ethanol (30 ml) at reflux for 2.5 h. The mixture was filtered through celite and the solvent evaporated. The residual oil was diluted with hexane (2 ml) and chromatographed on silica, eluting with 20% CHCl3 /hexane. 3-Chloro-5-ethylaniline (0.9 g) was isolated as a pure oil. δ (360 MHz, CDCl3) 1.19 (3H, t, CH3), 2.52 (2H, q, CH2), 3.20 (2H, s, NH2), 6.38 (1H, dd, Ar), 6.49 (1H, dd, Ar) and 6.58 (1H, dd, Ar).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][C:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: ClCCCCBr
Reactant: CCOC(=O)C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C1(CCCCCl)CCC1
Temperature: 0 °C

Procedure:
Compound 104b was prepared, likewise the procedure described for 104c, starting from LDA (prepared from BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) and iPr2NH (18.52 mL, 132 mmol, distilled from NaOH)), ethyl 1-cyclobutanecarboxylate (Török, B. et al. J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804) (14.05 g, 110 mmol) (the resulting mixture was allowed to warm to 0° C. and cooled again to −60° C.) and 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) to give, after purification by fractional distillation under reduced pressure, 104b (20.53 g, 86%) as a thin, colorless oil. bp: T=64-71° C. (p=0.001 Torr). 1H NMR: δ 4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR: δ 176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][N:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.NC1C=CC=CC=1.N1C=CC=CC=1.[CH:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)([CH3:38])[CH3:37]>CCO.C(Cl)Cl>[CH:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:13][N:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]3)=[CH:6][CH:5]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl[Sn]Cl
Solvent: Nc1ccccc1
Solvent: O
Solvent: CCO
Product: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Yield: 28.3 %

Procedure:
Following the same procedure as described in 46.5, 1-[3-(4-nitro-phenyl)-azetidin-1-yl]-propan-1-one (480 mg, 2.04 mmol) in EtOH (20 ml) was treated with SnCl2.2H2O (2.25 g, 9.97 mmol) and half of the resulting aniline in CH2Cl2 (15 ml) was then treated with pyridine (140 μl, 1.71 mmol) and 4-isopropyl-benzensulfonylchloride (230 μl, 1.28 mmol). Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 1:1) provided the title compound (140 mg, 36% for two steps) as a pale yellow gum.