Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=1)([OH:13])=[O:12].C[OH:39]>C1(C)C=CC=CC=1>[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:39])=[CH:32][CH:31]=1)([OH:13])=[O:12]
Reactant: N#Cc1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-iso-butylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 5.1 g. of 4-(15-carboxypentadecylamino)benzonitrile under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. Recrystallization from hexane affords 4-(15-carboxypentadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:43](=[O:44])[NH:42][C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=Nc1cccnc1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CN(c1ccc2c(c1)CCN2C(=O)Nc1cccnc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
220 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 166 mg potassium carbonate and 121 mg 3-pyridylisocyanate are added and the mixture is stirred overnight at ambient temperature. The reaction mixture is divided between water and dichloromethane. The aqueous phase is extracted twice with dichloromethane and the combined organic phases are dried on sodium sulphate. The solvent is eliminated in vacuo and the residue is taken up in 8 ml dichloromethane. 4 ml trifluoroacetic acid are added and the mixture is stirred for 2 hours at ambient temperature. The solvents are eliminated in vacuo and the residue is extracted from diisopropylether and petroleum ether. The solid is suction filtered and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>CS(C)=O>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[NH:21][C:20](=[O:23])[CH:19]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCBr
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCN1CCN(C)CC1
Reaction time: 15 h

Procedure:
1-Methylpiperazine (0.5 mL, 4.5 mmol) was added to a solution of 8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (150 mg, 0.32 mmol) and DMSO (2 mL) at room temperature. After 15 h, the reaction was placed under vacuum (˜0.1 Torr, 24h) to remove the excess amine. The resulting solution was purified by reverse-phase HPLC to give 4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 12.01 (br, 2H), 10.80 (br, 1H), 9.21 (s, 1H), 8.79 (s, 2H), 8.01 (d, 1H), 7.15 (d, 1H), 4.94 (s, 1H), 4.04 (t, 2H), 3.95 (s, 3H), 3.90-3.60 (br m, 4H), 3.60-3.34 (br m, 6H), 2.82 (s, 3H), 2.25 (m, 2H); MS (ESI): 492.3.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[K+:16]>O>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[K+:16].[K+:16]
Reactant: O=C(O)CCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCCC(=O)[O-]

Procedure:
A mixture of 100 g of sebacic acid, 116 g of a 48% aqueous solution of caustic potash and 1171 g of water was subjected to reaction conducted in the same manner as illustrated in Example 10 to obtain an aqueous solution of potassium sebacate having a pH value of 10.1 and containing 10.1% by weight of a solid matter. To this aqueous solution was added an aqueous solution of 177 g of silver nitrate in 200 g of water to effect a double decomposition reaction in the same manner as illustrated in Example 10 whereby 195 g of silver sebacate was obtained which had a silver content of 49.8% by weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23]OC(=O)C(OC)=O.C[O-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: COC(=O)C(=O)OC
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O

Procedure:
3-Methoxyandrosta-3,5-dien-17-one (I, 50.0 g) was dissolved in THF containing TEA (1 ml). Dimethyloxalate (55.5 ml) was added and the mixture cooled to 2°. Sodium methoxide (25%) in methanol (45.7 ml) was added slowly over 10 minutes. The ice bath was removed and the reaction warmed to 24° over five minutes with stirring. The mixture was stirred at 20°-25° for 55 minutes, then cooled to 5° over 10 minutes. Acetic acid (2.4 ml) was added, immediately followed by TEA (17.4 ml), then paraformaldehyde (7.49 g), followed by methanol (63 ml). The ice bath was removed and the mixture warmed to 20°-25° over 5 minutes. The mixture was stirred at 28° for 5 hrs and stored in a freezer (-20°) overnight. The mixture was then warmed to 20°-25° and stirred at 25° for 4 hrs for a total time of approximately 9.0 hrs at 20°-28°. Water (300 ml) and ethyl acetate (300 ml) were added, the mixture stirred and the layers separated. The organic layer was washed with saline (2×100 ml). The aqueous portion is backextracted with ethyl acetate (2×100 ml, washing each with 50 ml of saline). The organic phases are combined, concentrated under reduced pressure to an oil, taken up in methylene chloride (450 ml) and ethyl acetate (200 ml). This mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to a solid. Trituration of the solid with boiling methanol (100 ml) containing 1% TEA gives the title compound in crystalline form.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([C:31](=[O:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([C:31]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccncc1
Reactant: CCC(=O)c1nnc(-c2ccc(F)cc2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(c1ccncc1)c1nnc(-c2ccc(F)cc2)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To a solution of 4-iodo pyridine (0.142 g, 0.635 mmol) in THF (12 mL) at −78° C. was added n-BuLi in hexane (1.6 M, 0.582 mL, 0.8474 mmol) and the mixture stirred for 30 min A solution of 1-(5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)propan-1-one (0.1 g, 0.4237 mmol) in THF (8 mL) was added to above solution at −78° C. and the mixture stirred for 1 hour at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and diluted with water (25 mL). The reaction mixture was extracted with ethyl acetate (200 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by preparative TLC (using 5% methanol and dichloromethane) to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol as white solid (22 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ8.55 (d, 2H), 8.0-7.96 (m, 2H), 7.56 (d, 2H), 7.35 (t, 2H), 7.06 (s, 1H), 2.40-2.30 (m, 2H), 0.80 (t, 3H); LC-MS m/z calculated for [M+H]+316.08. found 316.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH:16]2[O:17][CH2:18][CH:19]([OH:20])[CH:15]2[O:14][CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH:16]3[O:17][CH2:18][CH:19]([OH:20])[CH:15]3[O:14][CH2:13]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC1COC2C(O)COC12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1nc(Cl)ncc1Cl)C1COC2C(O)COC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (484.9 mg, 2.64 mmol) and 6-(methylamino)hexahydrofuro[3,2-b]furan-3-ol (530.2 mg, 3.33 mmol) in EtOH (30 mL) was added Et3N (566.0 mg, 5.59 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc and water (1/1 (v/v), 100 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a pale yellow solid (760.2 mg, 94.0%).
Reaction SMILES: C(Cl)[Cl:2].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(Cl)(Cl)(=O)=O>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:21])[CH:19]([Cl:2])[CH3:20])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(Cl)C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a methylene chloride solution (20 mL) of 4.80 g (20 mmol) of p-(benzyloxy)propiophenone, 2.97 g (1.1 equivalents) of sulfuryl chloride was added at 15° C., followed by 16 hours of stirring. After 20 mL of water was added, methylene chloride was distilled off under a reduced pressure, and extraction was conducted by adding 40 mL of ethyl acetate. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. A colorless, oily substance (6.299 g) was thereby obtained. The oily substance was crystallized from 0.5 mL of ethyl acetate and 20 mL of hexane to obtain white crystals of 1-[4-(benzyloxy)phenyl]-2-chloro-1-propanone (4.3787 g, isolation yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][N:19](C(OCC5C=CC=CC=5)=O)[CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[C:4]([N:38]2[C:42]([CH3:43])=[N:41][CH:40]=[N:39]2)[CH:3]=1.Br.Br.CC(O)=O>O1CCOCC1.CC(O)=O>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][NH:19][CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[C:4]([N:38]2[C:42]([CH3:43])=[N:41][CH:40]=[N:39]2)[CH:3]=1
Reactant: Cc1ncnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCOC21CCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ncnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCOC21CCNC1
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a stirred solution of Example 37 (1.1358 g, 1.9265 mmol) in 1,4-dioxane (10 mL) was added 33 wt % HBr in AcOH (2 mL) at room temperature. Immediately upon addition of HBr/AcOH to the reaction, solids precipitated out of the reaction mixture. So, 3 mL of anhydrous MeOH was added and stirred for 2 h. Then, the reaction mixture was purified by preparative HPLC using water/MeOH containing 0.1% TFA to afford desired product (0.448 g, 41%) as white solid. 1H NMR (500 MHz, DMSO-d6) δ: 1205 (1H, s), 9.35-9.28 (1H, br s), 9.27-9.19 (1H, br s), 9.14 (1H, t, J=6.1 Hz), 8.12 (1H, s), 7.57-7.53 (2H, m), 7.48-7.44 (1H, m), 4.27 (2H, d, J=6.1 Hz), 4.09-4.05 (2H, m), 3.91-3.86 (2H, m), 3.70-3.49 (3H, m), 3.42-3.34 (1H, m), 2.66-2.59 (1H, m), 2.45-2.39 (1H, m), 2.33 (3H, s). HRMS (M+H) calcd for C21H23N7O4F: 456.1796; found: 456.1805.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CC[CH:33]([N:36]=[C:37]=NC2CCCCC2)CC1.CNC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([N:36]([CH3:37])[CH3:33])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 15 g of (2S,4R)-1-(benzyloxy-carbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid, 7.64 g of HOBT and 11.65 g of DCC in 250 ml of DCM is stirred for 1 hour at RT. The reaction mixture is cooled on an ice bath, dimethylamine gas is added by sparging for 10 minutes and this mixture is stirred for 3 hours at RT. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in saturated Na2CO3 solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained in the form of an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C.[NH2:47][CH2:48][C:49]1[C:58](=[O:59])[C:57]2[C:52](=[CH:53][C:54]([Cl:60])=[CH:55][CH:56]=2)[N:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:50]=1[C:67]([N:69]([CH3:71])[CH3:70])=[O:68]>CN(C=O)C>[CH3:70][N:69]([CH3:71])[C:67]([C:50]1[N:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:52]2[C:57]([C:58](=[O:59])[C:49]=1[CH2:48][NH:47][C:11]([C:10]1[CH:9]=[N:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)=[O:13])=[CH:56][CH:55]=[C:54]([Cl:60])[CH:53]=2)=[O:68]
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCOCC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Morpholinonicotinic acid (32.6 mg, 0.142 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (120 mg, 0.374 mmol) and triethylamine (100 mg, 0.137 mL, 0.988 mmol) were combined with DMF (4 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-(aminomethyl)-7-chloro-N,N-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxamide (intermediate C) (0.052 g, 0.156 mmol) was added. The reaction mixture was stirred at room temperature for 15 hr. The crude material was purified by flash chromatography (10% ethyl acetate-hexanes ramped to 100% ethyl acetate). MS calcd. for C29H28ClN5O4 [(M+H)+] 546.2, obsd. 546.0.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:11]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: O=C1CCN(c2nc(-c3ccccc3)no2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one (400 mg), cyclopropylamine (120 μL), sodium triacetoxyborohydride (420 mg) and glacial acetic acid (0.20 mL) in dichloromethane (7 mL) is stirred for two days at room temperature. Dichloromethane is added and the mixture is washed with aqueous K2CO3 solution. The organic phase is dried over Na2SO4 and concentrated in vacuo to afford the title compound. TLC: rf=0.30 (silica gel, CH2Cl2/MeOH 95:5); Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH:10]=[CH:9][CH2:8][N:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CC=CCN(CC2CC2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCCN(CC2CC2)C1=O
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [3-cyclopropylmethyl)-2-oxo-2,3,4,7-tetrahydro-1H-1,3-diazepin-1-yl]acetate from Step C (250 mg, 0.89 mmol) in EtOH (10 mL) was added 10% Pd/C (9.5 mg) and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 90 min, the catalyst was filtered off and the filtrate was concentrated to yield the title compound. MS: m/z=283 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:18]=2)[CH:14]=1.[Br:43]N1C(=O)CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]1[C:10]([Br:43])=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[N:18]=2)[CH:14]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc(Br)n2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 1-(1-(3,5-difluorobenzyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (72.0 mg, 0.12 mmol) was dissolved in methylene chloride (3.0 mL) and cooled to −78° C. To this was added N-bromosuccinimide (18.3 mg, 0.11 mmol) and the mixture allowed to stir at −78° C. for 30 min. After warming to room temperature, the solvent was removed and the residue purified by column chromatography to afford 30 mg (40%). 1H-NMR (CD3OD, 300 MHz) δ −0.06 (s, 9H), 0.89 (m, 2H), 1.33 (s, 9H), 2.44 (s, 3H), 3.15-3.25 (m, 1H), 3.57-3.66 (m, 2H), 4.80-5.09 (m, 2H), 6.26 (m, 2H), 6.47-6.66 (m, 2H), 7.12 (s, 1H), 7.20 (s, 1H), 7.91 (s, 1H). Mass spec.: 678.3 (MH)+.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:51][C:48]3[CH:49]=[N:50][C:45]([CH3:44])=[CH:46][CH:47]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(N)cn1
Product: Cc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cn1

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-methyl-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=370.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH:14]([CH3:21])[CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.ClCCl>[O:30]1[C:17]([CH3:20])([CH2:18][CH3:19])[CH:16]1[CH2:15][CH:14]([CH3:21])[C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=1
Reactant: CCC(C)=CCC(C)C(C)=CCOc1ccc(CC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(OCC=C(C)C(C)CC2OC2(C)CC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10 g. of p-ethylphenyl 3,4,7-trimethyl-2,6-nonadienyl ether are dissolved in 110 ml. of dichloromethane and treated portionwise at -10° C. with 7.8 g. of 80% m-chloroperbenzoic acid. After completion of the treatment, the mixture is stirred for a further 2 hours at 0° C., shaken out with 10% sodium sulfite solution, 1-N sodium hydroxide solution and water, dried over sodium sulfate and evaporated. There is obtained pure 6,7-epoxy-1-(p-ethylphenoxy)-3,4,7-trimethyl-2-nonene; NMR (CDCl3): 7.25-6.7 ppm (AB-quartet of the four aromatic protons); 5.5 ppm (a vinyl proton at C-2); 4.52 ppm doublet of the --O--CH2 group); 2.59 ppm (quartet of the aromatic-bound --CH2 group); 2.8-2.2 ppm (multiplet of the protons at C-4 and C-6); 1.65 ppm (wide singlet of the methyl group at C-3); 1.78-0.8 ppm (complicated multiplet of 19 protons).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1.I[CH:22]([CH3:24])[CH3:23].[H-].[Na+].O>O1CCOCC1>[CH:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: O=c1[nH]c2cc(C3CCCNC3)nn2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CCCC(c2cc3[nH]c(=O)c4ccccc4n3n2)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 19 (0.07 g, 0.3 mmol) and 2-iodopropane (0.09 mL, 0.9 mmol) in dioxane (2 mL) and was treated with sodium hydride (0.01 g, 0.4 mmol). The mixture was stirred overnight at 65° C., cooled to ambient temperature, treated with water and concentrated. The residue was purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.81-7.87 (m, 1H), 7.42-7.47 (m, 1H), 5.88 (s, 1H), 3.21 (dt, J=11.3, 1.9, 1H), 2.99-3.10 (m, 2H), 2.92 (dt, J=13.2, 6.6 Hz, 1H), 2.51 (t, J=11.0 Hz, 1H), 2.38 (td, J=11.5, 2.8 Hz, 1H), 2.09 (ddd, J=9.0, 3.8, 3.7 Hz, 1H), 1.83-1.92 (m, 1H), 1.70-1.82 (m, 1H), 1.59 (qd, J=12.3, 4.0 Hz, 1H), 1.14-1.19 (m, 6H).