Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:19][C:13]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(Br)CCCCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\OC1(C)CCCCC1)C(C)=O
Yield: 68.3 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.18 g, 20 mmol) and 1-bromo-1-methylcyclohexane (3.54 g, 20 mmol) in dry dioxane (15 ml) were stirred together in the dark and silver trifluoromethanesulphonate (5.13 g, 20 mmol) was added portionwise over 4 h. After a total of 100 h the mixture was filtered through Kieselguhr and the residue was washed well with dioxane. The filtrate was evaporated in vacuo, toluene was added and evaporated in vacuo and the residual oil was dissolved in ethyl acetate and washed with dilute aqueous NaHCO3, followed by water and brine. Ater drying (MgS4) the ethyl acetate was evaporated in vacuo and the residual oil was chromatographed on silica gel, to give the title compound as a yellow oil (3.49 g; 69%); νmax (CH2Cl2) 2945, 1740, 1685, 1370, 1320, 1235, 1070 and 1005 cm-1 ; δH (60 MHz, CDCl3) 1.35 (6H, s superimposed on t), 1.4-2.0 (10H, m), 2.37 (3H, s), 4.55 (2H, q, J 7 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[O:9]1CCOCC1>O>[S:6]1[CH:7]=[CH:8][C:4]([C:1]([CH:2]=[O:9])=[O:3])=[CH:5]1
Reactant: C1COCCO1
Reactant: CC(=O)c1ccsc1
Solvent: O
Product: O=CC(=O)c1ccsc1

Procedure:
3-Acetylthiophene (20.0 g., 0.159 mol) and SeO2 (19.4 g., 0.175 mol) were dissolved 100 ml. dioxane and 8 ml. H2O by warming to 35°, then heated at reflux 16 hours. The reaction mixture was cooled, filtered and the filtrate stripped to a sludge (the hydrate of title product in crude form). The latter was distilled at reduced pressure to yield title product contaminated with about 10% starting material, 8.53 g.; tlc (5:3 hexane:ethyl acetate) Rf 0.27 (title product) and 0.59 (3-acetylthiophene). The latter was chromatographed on silica gel with 5:3 hexane:ethyl acetate as eluant. Clean product fractions were combined stripped to a solid, triturated with hexane, filtered and the solids (5.60 g.) sublimed to yield purified title product, 3.20 g.; tlc Rf 0.27 as above; sublimation point 70°/1 mm; ms: parent 141, base 111.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[C:40]=1[CH2:41][NH2:42]>>[CH3:48][O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:39]([O:38][CH3:37])[C:40]=1[CH2:41][NH:42][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: COc1cccc(OC)c1CN
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: COc1cccc(OC)c1CNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2,6-dimethoxybenzylamine according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ3.76 (s, 6H), 4.43 (d, J=4.2 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.2 Hz, 1H), 7.23 (s, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.79 (m, 3H), 8.07 (s, 1H), 8.13 (br s, 1H), 11.27 (s, 1H), 12.76 (s, 1H); APCI−MS m/z 532 (M+Na)+; Anal. Calcd for C24H23N5O6S.1/2H2O: C, 55.59; H, 4.67; N, 13.51; S, 6.18. Found: C, 55.69; H, 4.64; N, 13.61; S, 6.09.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:47]=[CH:48][C:49]([CH2:50][OH:51])=[CH:52][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(CO)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(CO)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminobenzylalcohol as the aniline component. (84%, MS=500.2 (M+H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH2:28][C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])[N:21]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Yield: 42.5 %

Procedure:
To a mixture of the amidine of step 1 (1.9 g, 6.23 mmol) and sodium bicarbonate (1.05 g, 12.46 mmol) in isopropanol (150 ml), 3-bromo-1,1,1-trifluoroacetone (0.97 ml, 9.34 mmol) was added. After heating at 85–90° C for 48 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (4.25 g) was purified by chromatography (silica gel, methylene chloride/methanol/ammonium hydroxide, 95/5/0.5) to give the 4,5-dihydro-imidazole (1.1 g, 42%) as a white solid: Anal. Calcld. for C17H16N3SO4F3.0.5 EtOAc: C, 49.67, H, 4.39, N, 9.15. Found: C, 49.80, H, 4.06, N. 9.33.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>O>[CH2:45]1[CH2:46][O:47][CH:7]2[CH:8]([C@@H:9]([C@@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:21]1
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 3.4 g. of ethyl 15-hydroxy-9-oxo-prostanoate (Example 50) in 85 ml. of benzene containing 30 mg. of p-toluenesulfonic acid monohydrate and 2 ml. of ethylene glycol is stirred at the reflux temperature for 18 hours. The water formed is removed by means of a Dean-Stark distilling receiver. The cooled solution is washed with 5% aqueous sodium carbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3.78 g. (99%) of oil; λ max. 2.93 (hydroxy group) and 5.77 μ (ester carbonyl group).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[CH2:53][NH2:54]>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:54][CH2:53][C:49]4[S:48][CH:52]=[CH:51][CH:50]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccs1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccs1
Yield: 82 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with thiophen-2-ylmethanamine, the title compound was obtained as a colorless solid in 82% yield: mp 128-131° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m, 3H), 7.06-6.93 (m, 4H), 6.08 (s, 1H), 6.01 (t, J=5.4 Hz, 1H), 4.73 (d, J=5.4 Hz, 2H), 4.42 (s, 2H), 3.82-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 162.4 (d, JC-F=246.4 Hz), 155.8, 142.5, 141.4, 140.9, 131.8 (JC-F=3.1 Hz), 130.0 (JC-F=8.2 Hz), 126.9, 126.1, 125.2, 119.3, 115.7 (JC-F=21.5 Hz), 112.4, 47.4, 42.7, 41.4, 38.5, 16.1; MS (ES+) m/z 452.3 (M+23).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:13][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2[nH]ccc2c1

Procedure:
To a solution of 5-indole carboxylic acid (5.08 g, 31.5 mmol) in a 1:1 mixture of methanol/methylene chloride (40 mL) was added (trimethylsilyl)diazomethane (33 mL, 2 M solution in hexanes) in portions over 15 min. The yellow colored solution was concentrated on the rotoevaporator to provide methyl-5-indole carboxylate as a white powder (5.5 g).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(O)C.[N+]([NH:31][C:32](N)=[O:33])([O-])=O>O>[NH2:31][C:32]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:33]
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
A mixture of 4.89 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, 50 ml of 95% ethanol and 2.1 g of nitrourea was refluxed at 70° C. until the evolution of gas had ceased. After refluxing for an additional 30 minutes, the mixture was cooled, treated with 200 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 3.5 g (64.81%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 155°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:34][CH2:33][C:20]4([N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][N:22]([CH3:31])[C:21]4=[O:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:68][N:69]([CH3:73])[CH2:70][CH2:71][NH2:72]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:34][CH2:33][C:20]4([N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:23][N:22]([CH3:31])[C:21]4=[O:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:72][CH2:71][CH2:70][N:69]([CH3:73])[CH3:68])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CN1CN(c2ccccc2)C2(CCN(C(=O)c3cn(CC(=O)O)c4cc(Cl)ccc34)CC2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)Cn1cc(C(=O)N2CCC3(CC2)C(=O)N(C)CN3c2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of [6-chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-acetic acid in DMF was treated sequentially with 1 eq. of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1 eq. of N,N-diisopropylethylamine and 1 eq. of N,N-dimethylethylenediamine. The mixture was shaken at room temperature for 12 h, concentrated and purified by prep. HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[CH:33][C:20]1[NH:21][CH:22]=[C:23]([C:24]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[C:19]=1[CH3:18])[C:11](=[O:17])[NH:12]2
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3F)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(2-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 36%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>C(Cl)Cl>[C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:28])[CH2:27][CH2:26][N:25]([S:42]([C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)(=[O:44])=[O:43])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCNCC1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCN(S(=O)(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of 6-benzenesulfonyl-1-(4-methyl-piperidine-4-yl)1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (60.0 mg, 0.15 mmol) was dissolved in DCM, triethylamine (28.0 μL, 0.20 mmol) was added followed by pyridine-3-sulfonyl chloride (32.0 mg, 0.18 mmol) and the reaction stirred at room temperature for 16 hr. The reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 74 mg (91%) of 6-benzenesulfonyl-1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method H, ESI): RT=3.52 min, m+H=538.3; 1H NMR (400 MHz, DMSO): δ 9.21 (s, 1H), 8.84 (m, 2H), 8.19 (m, 3H), 8.10 (m, 1H), 7.74 (d, 1H), 7.62 (m, 3H), 7.31 (d, 1H), 3.45 (d, 2H), 2.82-2.67 (m, 4H), 2.33 (m, 2H), 1.69 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.CN.Cl.[BH3-][C:23]#[N:24].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][CH3:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Benzylpiperidin-4-one (5.0 g, 26.315 mmol, 1.0 eq.) was dissolved in MeOH (78 ml); AcOH (0.2 ml) and CH3NH2.HCl (2.6 g, 39.47 mmol, 1.5 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.3 g, 52.63 mmol, 2.0 eq.) was then added in portions at 0° C. and the mixture was stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure. The residue was taken up in sat. sodium hydrogen carbonate solution (150 ml) and extracted with DCM (2×200 ml). The combined org. phases were dried over sodium sulfate, concentrated and used in the next stage without being purified further. Yield: 92% (5.0 g, 24.509 mmol)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[CH:33]2)[CH:20](N1C(=O)CCC1=O)O>C(O)CO>[CH3:17][NH:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:19]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:20][N:1]=3)[N:4]=2)=[CH:13][N:12]=1)=[O:15]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Reactant: CNC(=O)c1ccc(-c2cnc(N)nn2)cn1
Solvent: OCCO
Product: CNC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(3-amino-1,2,4-triazin-6-yl)-N-methylpyridine-2-carboxamide (Step 1, 6.5 g, 0.022 mol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (8.71 g, 0.0273 mol, Example 1, Step 7) in 1,2-ethanediol (100 mL) was stirred at 120° C. overnight. The reaction mixture was concentrated. The mixture was neutralized to pH=10 with methylamine in THF solution (2.0M), and then purified by flash chromatography on a silica gel column with 5% MeOH in dichloromethane to afford the desired product which was contaminated with some starting material. The product was dissolved in 10% MeOH in dichloromethane, and concentrated to a volume of about 2 mL. The resulted solid was filtered, washed with MeOH (2 mL) to afford the pure product (4.50 g, 50%). The product was treated with 2N HCl (aqueous) and acetonitrile, and dried by lyophilization to give the desired product as the HCl salt. LCMS (M+H)+: m/z=396.4. 1H-NMR (400 MHz, DMSO-d6): 9.40 (s, 1H), 9.27 (s, 1H), 9.20 (d, J=5.5 Hz, 1H), 9.10 (d, J=8.0 Hz, 1H), 8.64 (d, J=8.0 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.20 (d, J=8.0, Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 5.5 Hz, 1H), 4.76 (s, 2H), 2.81 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:30][CH2:29][CH2:28]1>CN(C1C=CN=CC=1)C.CC#N>[N:27]1([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: C1CNC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC3)ccc2n1CC1CCC(F)(F)CC1
Yield: 68.9 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (122 mg, 0.3 mmol), azetidine (41 uL, 34 mg, 0.6 mmol) and DMAP (73 mg, 0.6 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 88 mg (69%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.49-1.63 (m, 2 H), 1.65 (s, 9 H), 1.69-1.93 (m, 4 H), 1.98-2.19 (m, 4 H), 2.21-2.34 (m, 1 H), 3.73-3.82 (m, 4 H), 4.51 (d, J=7.42 Hz, 2 H), 7.84 (dd, J=8.59, 1.76 Hz, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 8.13 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=426.2.
Reaction SMILES: [Cl:1][C:2]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([NH:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Si:29]([O:36][CH2:37][CH:38]=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:38][CH2:37][O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: CNC1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Yield: 99.9 %

Procedure:
The title compound (0.390 g, 99%) was prepared from (±)-2-chloro-N-[[1-(methylamino)cyclopentyl](phenyl)methyl]-3-(trifluoromethyl)benzamide (0.282 g; 0.686 mmol), (tert-butyldimethylsilyloxy acetaldehyde (90%; 0.265 g; 1.52 mmol) and sodium triacetoxyborohydride (0.290 g; 1.52 mmol) in DCM (5 ml) in a similar manner to that described in E30. Mass Spectrum (Electrospray LC/MS). Found 569 (MH+). C29H4035ClF3N2O2Si requires 568. Ret. time: 3.04 min.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH3:12][N:11]1[C:3]2[C:2]([NH:14][CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:19][OH:20])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:13])=[N:10]1
Reactant: CC(C)[C@H](N)CO
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC(CO)C(C)C)c2c(n1)c(C)nn2C
Reaction time: 50 h
Yield: 45.6 %

Procedure:
A mixture of 8 g (0.04 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 3), 4.5 g (0.045 mol) of L-valinol (2-amino-3-methyl-1-butanol) and 8 ml of triethylamine in 50 ml of dimethylformamide is stirred at 50°-55° C. for 50 hours and evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with a saturated solution of sodium bicarbonate, dried over MgSO4, and evaporated in vacuo. The residue is stirred in pet ether to give 4.8 g (45%) of 2-[1,3,5-trimethyl-1H-pyrazolo[4,3-d]-pyrimidine-7-yl]amino-3-methyl-1-butanol, mp 166°-168° C. from acetonitrile.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][NH:19][C:18]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])=[N:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[C:31]([N:17]1[CH:16]([C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH2:20][N:19]=[C:18]1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])(=[O:33])[CH3:32]
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CN1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N1C(c2c(F)cccc2F)=NCC1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 7.2 %

Procedure:
1.5 g (3.6 mmol) of 4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-1H-imidazole (for example from Example V-1) were dissolved in 20 ml of toluene, admixed with 1.7 ml (1.84 g; 18 mmol) of acetic anhydride and boiled under reflux for 1 h. The mixture was then concentrated and the residue was recrystallized from a mixture of cyclohexane and ethyl acetate. This gave 1.07 g (65% of theory) of 1-acetyl-4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-1H-imidazole (I-7a). 0.6 g of concentration residue from the mother liquor was separated by column chromatography (silica gel; Ø=3cm, 1=30 cm; cyclohexane:ethyl acetate=5:1). 0.12 g (7% of theory) of 3-acetyl4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-3H-imidazole (I-7b) was obtained as second fraction as an oil.