Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.Cl.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)=[CH:34][CH:33]=1.[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69]([N:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)=[CH:43][N:42]=2)[CH2:49][CH2:48]1)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Fc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 85.9 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine dihydrochloride (0.108 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.147 g), to yield the title compound as a pale green gum (0.167 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=[C:12]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])[N:13]=1
Reactant: NC(CO)CO
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Product: O=c1ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc2n1-c1ccccc1F

Procedure:
The product of Example 49, and serinol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 2.91 (br s, 2H), 3.39 (m, 1H), 3.55 (m, 4H), 6.05 (br s, 1H), 6.33 (d, 1H, J=9.7 Hz), 6.21 (m, 51), 7.39 (m, 4H). LC MS (m/e)=425 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:30][C:7]1[C:8](=[O:24])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)cc2=O)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate (350 mg, 0.87 mmol) (1.0 g, 2.5 mmol) was added into 150 ml of dichloromethane followed by addition of N-bromo succinimide (500 mg, 2.8 mmol). The solution was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution (300 ml) was added into the reaction mixture and it was transferred to a separatory funnel. The product was extracted with ethyl acetate (500 ml X2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, CDCl3) δ 9.08 (app d, J=2.15 Hz, 1H), 8.21 (dd, J=6.04, 2.15 Hz, 1H), 7.55 (app qt, J=6.31 Hz, 1H), 7.41 (d, J=6.31 Hz, 1H), 6.91 (m, 1H), 6.84 (m, 1H), 6.02 (s, 1H), 5.42 (s, 2H), 5.19 (s, 2H), 3.91 (s, 3H), 2.45 (s, 3H); LC/MS, tr=2.85 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0415 (M+H calcd for C21H18BrF2N2O4 requires 479.0413).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(B(O)O)C=CC=CC=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Agent: OB(O)c1ccccc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccccc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-phenylnaphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 79% yield using phenylboronic acid as the reagent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=O)[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH2:31]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:19])[N:31]([CH3:30])[C:12]2=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2C
Temperature: 22 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of intermediate 3, ethyl 5-(benzyloxy)-1-(methoxycarbonylmethyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.790 g, 1.86 mmol) in tetrahydrofuran (10 ml) was treated with a 2 M solution of methylamine in tetrahydrofuiran (10 ml, 20.0 mmol) and the resulting mixture was stirred at 22° C. for 1 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by recrystallization of the solid residue from ethyl acetate/hexane gave 0.705 g (83% yield) of the title ester as white crystals; mp 167° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 3.29 (3H, s, NCH3), 4.37 (2H, q, J=7.2 Hz, OCH2), 4.55 (2H, s, CH2), 5.23 (2H, s, OCH2), 7.3–7.5 (5H, m, aromatics). Anal. Calcd for C17H17N3O5: C, 59.47; H, 4.99; N, 12.23. Found: C, 59.5, H, 5.07; N, 12.40.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1.[Br:14][C:15]([CH2:17]Br)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:17][C:15]([Br:14])=[CH2:16])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1
Reactant: C=C(Br)CBr
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Br)COc1ccc2c(C)cc(=O)oc2c1
Yield: 89 %

Procedure:
4-Methyl-7-hydroxycoumarin (2.00 g., 11.4 m mole) was refluxed with freshly-distilled 2,3-dibromopropene (2.72 g., 13.6 m mole), anhydrous potassium carbonate (3.15 g., 22.8 m mole), and acetone (80 ml.) for four hours. The reaction mixture was treated as described for the preparation of Example I, Part 1-A to obtain 4-methyl-7-(2'-bromoallyloxy) coumarin as an off-white solid (3.70 g.) that contained some excess 2,3-dibromopropene. Recrystallization of a portion (500 mg.) from ligroin (b.p. 100°-120° C.) gave needles (394 mg., 89% yield) of m.p. 109.5°-110.5° C. An analytical sample of m.p. 110°-111° C. was obtained by recrystallization from methanol.
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=O)[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2.[CH2:20]([CH2:22][NH2:23])[OH:21]>C1(C)C=CC=CC=1>[OH:21][CH2:20][CH2:22][N:23]1[C:18](=[O:19])[C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[C:14]=2[C:13](=[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[CH:6]3)[C:15]1=[O:17]
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Reactant: NCCO
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCO
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A mixture of 1.51 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride and 0.4 g (6.5 mmol) of ethanolamine in 50 ml of toluene is refluxed for 5 hours and then cooled to room temperature. The solid is filtered, dried and crystallized from toluene to give 1.5 g (85%) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione. M.p. 211° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([NH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(C)(=O)=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl) cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (260 mg) in dichloromethane (3 mL) were added triethylamine (0.15 mL) and methanesulfonyl chloride (56 μL) successively. The solution was stirred at room temperature for 6 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3 to 1:1 to 1:2] to give the title compound (214 mg).
Reaction SMILES: CO.[CH3:3][NH2:4].C(O[C:8]([C:10]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:33]4[CH:32]=[CH:31][S:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[N:12]([CH2:34][CH:35]=[CH2:36])[N:11]=1)=[O:9])C>CO>[CH3:3][NH:4][C:8]([C:10]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:25]3[C:33]4[CH:32]=[CH:31][S:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)[N:12]([CH2:34][CH:35]=[CH2:36])[N:11]=1)=[O:9]
Reactant: CN
Reactant: C=CCn1nc(C(=O)OCC)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Solvent: CO
Product: C=CCn1nc(C(=O)NC)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
40% methylamine methanol solution (5 ml) was added to a methanol solution (5 ml) of 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 1.1 mmol) and the mixture was stirred at room temperature for 3 days. The solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid methylamide (0.32 g, 67% yield) as white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:35]([OH:37])[CH3:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:35]([C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34])(=[O:37])[CH3:36]
Reactant: CC(O)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(=O)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 87.1 %

Procedure:
206 mg (0.398 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-(1-hydroxyethyl)-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 94 (1) was suspended in 20 mL of toluene, 348 mg (3.98 mmol) of manganese dioxide was added and the mixture was heated at reflux for 2 hours. The reaction solution was filtered, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetonitrile=50:1) to give 179 mg of 7-acetyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 87%).
Reaction SMILES: C[O:2]/[CH:3]=[CH:4]/[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1.C1COCC1>CO>[O:2]=[CH:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1
Reactant: CO/C=C/C1Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CC=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (E)-tert-butyl 3-(2-methoxyvinyl)-3,4-dihydroquinoline-1(2H)-carboxylate (225 mg, 0.778 mmol) in THF (5 mL) dilute HCl (0.2 ml, 6.58 mmol) was added. The reaction mixture was stirred overnight at RT. The progress of reaction was monitored by TLC. After completion of reaction methanol was evaporated under reduced pressure. Further it was purified by flash column chromatography (15% ethyl acetate in hexane) to get the title compound (160 mg, 30.4% yield); m/z-297.6 as Na+1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2oc(NC3CCNCC3)nc2c1
Yield: 93.1 %

Procedure:
To a solution of 4-(5-cyano-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.62 g, 19.33 mmol, 1.0 equiv) in dichloromethane (100 mL) was added trifluoro-acetic acid (7.4 mL, 11.03 g, 96.7 mmol, 5.0 equiv). After stirring under Ar at rt for 18 h excess trifluoro-acetic acid was removed under reduced pressure and the crude solid taken up in dichloromethane (100 mL) and water (100 mL). The pH was adjusted to 10 by addition of a conc. solution of K2CO3 and the solution extracted with dichloromethane/2-propanol (4:1, 3×50 mL). The combined organic phases were dried over MgSO4, the organic solvent evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) containing 33% of NH4OH to yield 4.36 g (93%) of the title compound. MS (ESI): 243.1 [M+H]+.
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][CH:8]([CH2:10][C:4]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:20]C(N)=O.[ClH:24]>O>[ClH:24].[NH2:20][C:2]12[CH2:11][C:6]3([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][CH:8]([CH2:10][C:4]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC(N)=O
Reactant: CCCCC12CC3CC(Br)(C1)CC(CCCC)(C3)C2
Agent: Cl
Solvent: O
Product: CCCCC12CC3CC(N)(C1)CC(CCCC)(C3)C2
Reaction time: 0.17 h

Procedure:
3.27 grams of 1-bromo-3,5-di-n-butyl-adamantane were warmed with 1.2 grams of urea for 160 minutes at 165° C. The heating was performed in a closed vessel in a thermostatically controlled oil bath. After cooling, the reaction product was suspended in 50 ml. water. The water phase was brought to a pH of about 4 through dropwise addition of concentrated hydrochloric acid. The water phase was then extracted with two 10-ml. portions of ether, and brought to a pH of about 13 by dropwise addition of sodium hydroxide. The alkaline solution was stirred for about 10 minutes, after which the aqueous alkaline phase was extracted with four 10-ml. portions of benzene. The combined benzene extracts were dried over fused potassium sulfate. 1-amino-3,5-di-n-butyl-adamantane hydrochloride was precipitated by exposure to dried hydrogen chloride gas. Yield: 1.86 grams (62% of the theoretical yeild).
Reaction SMILES: [CH2:1]([N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:8]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:31]([C:33]1[O:37][C:36]([C:38](Cl)=[O:39])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl>[CH2:1]([N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:38]([C:36]2[O:37][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[O:39])=[C:9]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:8]=1)[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CCN(C)CCCc1ccc(N)c(N2CCC(C)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C)CCCc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCC(C)CC2)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 4-[3-(ethyl-methyl-amino)-propyl]-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in the previous step, 32 mg, 0.11 mmol) in DCM (2 mL) at 0° C. was added DIEA (48 μL, 0.27 mmol) followed by 5-cyano-furan-2-carbonyl chloride (as prepared above, 22 mg, 0.16 mmol). The reaction was allowed to warm to RT overnight, at which time it was diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (10 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (10% MeOH—CHCl3) afforded 20 mg (45%) of the title compound as an oily amber solid. 1H-NMR (CDCl3; 400 MHz): δ 9.69 (s, 1H), 8.38 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3.6 Hz), 7.05 (d, 1H, J=2.0 Hz), 7.00-6.97 (m, 1H), 6.91 (d, 1H, J=4.0 Hz), 3.01-2.98 (m, 2H), 2.78-2.64 (m, 7H), 2.50 (s, 3H), 2.04-1.98 (m, 2H), 1.89-1.85 (m, 2H), 1.63-1.46 (m, 5H), 1.25 (t, 3H, J=4.6 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.93-0.89 (m, 2H). Mass spectrum (ESI, m/z) calcd for C24H32N4O2, 409.2 (M+H). found 409.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH:19]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:20]43[C:36]3[C:28](=[CH:29][C:30]5[CH2:31][CH2:32][NH:33][C:34]=5[CH:35]=3)[O:27][CH2:26]4)=[O:18])=[CH:13][CH:12]=2)=[C:7]([CH3:37])[CH:6]=1)=O.O.[NH2:39][NH2:40].O>CO>[NH:39]([C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH:19]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:20]43[C:36]3[C:28](=[CH:29][C:30]5[CH2:31][CH2:32][NH:33][C:34]=5[CH:35]=3)[O:27][CH2:26]4)=[O:18])=[CH:13][CH:12]=2)=[C:7]([CH3:37])[CH:6]=1)=[O:2])[NH2:40]
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)C3CN(C)CCC34COc3cc5c(cc34)NCC5)cc2)c(C)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NN)ccc1-c1ccc(C(=O)C2CN(C)CCC23COc2cc4c(cc23)NCC4)cc1

Procedure:
A solution of 5'(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E22, 0.75 g, 1.5 mmole) in methanol (25 ml) was treated with hydrazine monohydrate (1.05 ml) and heated under reflux for 18 h. The reaction mixture was allowed to cool, then poured into water (50 ml) and the solid which precipitated out was filtered off and dried (0.61 g, 81%). A 50 mg portion was purified by preparative TLC on silica gel eluting with 20% methanol/chloroform to afford the title compound as a white solid mp. 130-135° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:13]Br.Br>C(O)(=O)C.O>[Br:13][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: BrBr
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CC(Br)C2=O

Procedure:
1-Oxoindane-5-carbonitrile is brominated with bromine in glacial acetic acid with addition of a catalytic amount of 48% strength HBr solution in water and affords 2-bromo-1-oxoindane-5-carbonitrile with a melting point of 115-118° C.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CCOCC.O>[Cl:31][CH2:32][C:33]([N:9]([CH2:8][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:1]1)[C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[O:34]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(CC)c1NCC1OCCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccc(CC)c1N(CC1OCCCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-dioxepan-2-ylmethyl)-2,6-diethylaniline (26.3 grams), sodium bicarbonate (15 grams), dioxane (30 ml) and water (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0°C and chloroacetyl chloride (15 grams) is added, with stirring, over a period of about 15 minutes. After the addition is completed stirring is continued for a period of about 1 hour. After this time ether (100 ml) is added to the mixture and the resulting solution is washed with water. The washed solution is then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue is recrystallized to yield the desired product N-α-chloroacetyl-N-(1,3-dioxepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][S:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[N:18][N:17]=2)[CH2:13][O:12]1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:10][C:11]([CH3:13])([OH:12])[CH2:14][S:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[N:18][N:17]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(CSc2nnnn2-c2ccccc2)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)(CSc1nnnn1-c1ccccc1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 69 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (1.2 g, 8.13 mmol), 5-(2-methyloxiran-2-ylmethylthio)-1-phenyl-1H-tetrazole (1.9 g, 7.65 mmol), sodium acetate (700 mg, 8.53 mmol) and ethanol (20 ml) was stirred under reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution twice, then washed with water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-(1-phenyl-1H-tetrazol-5-ylthio)propane-2-ol to afford (2.1 g, yield 69%) as a light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9])[CH:6]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:14])([CH3:13])[CH2:8][OH:9])[CH:6]=1
Reactant: CCOC(=O)C(C)(C)n1cc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a solution of ethyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate (0.8 g, 3.06 mmol) in MeOH (10 mL) was added sodium borohydride (0.348 g, 9.19 mmol). The reaction was stirred at room temperature for 3 h and quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.6 g, 89% yield) as a white powder. LCMS, [M+H]+=219.0.