Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([CH3:59])[CH2:22][O:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]3[N:55]=[C:56]([CH3:58])[N:57]=[C:31]23)[CH2:26][CH2:25]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH:21]([CH3:59])[CH2:22][O:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:51][C:4](=[O:7])[O:5][N:3]=4)=[CH:42][CH:43]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]3[N:55]=[C:56]([CH3:58])[N:57]=[C:31]23)[CH2:26][CH2:25]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O[Si](C)(C)C(C)(C)C)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2nc(C)nn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogen carbonate (0.68 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-{[tert-butyl(dimethyl)silyl]oxy}propoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.079 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was solidified with diisopropyl ether to give the title compound as a colorless solid (0.13 g, 54%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C@@H:13]2C[C@H:14]2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C@@H:13]2[CH2:14][C@H:1]2[C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 2 h

Procedure:
In a dry 250 ml round-bottomed flask was added oxalyl chloride (0.90 ml, 1.8 mmol) to 8A (0.60 g, 3.5 mmol) in CH2Cl2 at room temperature to give a yellow solution. In 2 hours, the reaction was complete. The crude mixture was concentrated in vacuo and residual TFA was removed azeotropically with toluene 3 times to give the desired product (1R,2R)-2-phenylcyclopropanecarbonyl chloride (8A-1), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:22]=1[CH2:21][CH2:20][NH:19][C:18]2=[O:17])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@H:4]([OH:43])[CH2:5][NH:6][C:7](=[O:42])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=2)=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[CH:21]1([C:18]2[CH:17]=[CH:16][C:15]([CH:14]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([S:37][C:38]([F:41])([F:39])[F:40])=[CH:33][CH:32]=3)=[O:29])[C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C@@H:4]([OH:43])[C:3]([OH:44])=[O:2])=[O:42])=[CH:9][CH:10]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(C(NC(=O)Nc2ccc(SC(F)(F)F)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)NC(c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester (0.32 g, 0.508 mmol) was dissolved in ethanol (15 mL) and sodium hydroxide (4 N, 0.76 mL, 3.05 mmol) was added. The reaction mixture was stirred for 1.5 hour. The reaction was evaporated and added water (15 mL) and acidified with hydrochloric acid (4 N, 0.8 mL). The mixture was extracted with ethyl acetate (20 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL) and the combined organic phases were washed with water (3×10 mL), dried over magnesium sulphate, filtered and concentrated to give the title compound (0.3 g).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][N:24]=3)=[CH:17][C:16]=2[CH3:32])[CH2:10][CH2:9]1)=O)(C)C.[ClH:34].CO>>[ClH:34].[ClH:34].[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](/[CH:22]=[CH:21]/[C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:33])=[C:16]([CH3:32])[CH:17]=2)=[N:24]1
Reactant: Cc1cc(/C=C/c2n[nH]c3ccccc23)ccc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: Cc1cc(/C=C/c2n[nH]c3ccccc23)ccc1C(=O)N1CCNCC1
Yield: 77 %

Procedure:
(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoyl}piperazine-1-carboxylic acid 1,1-dimethylethyl ester (980 mg, 2.20 mmol) obtained in Step 1, was treated with 10% hydrogen chloride-methanol solution to obtain Compound 95 (585 mg, 77%).
Reaction SMILES: C([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)C1C=CC=CC=1.[I-:29].[K+]>>[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][C@@H:17]([I:29])[C:18]2=[O:28])[CH2:10]1.[I:29][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: C[C@]12CC[C@H](OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [I-]
Agent: [K+]
Product: C[C@]12CC[C@H](I)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](I)C[C@@H]12

Procedure:
Reaction of 3β,17-dihydroxyandrosta-5,16-diene 17-acetate 1 with mercuric acetate followed by treatment with potassium iodide yields the C-16αiodide which hydrolyses with acid to yield 3β-hydroxy-16α-iodoandrost-5-en-17-one, 2d. Reaction of 2d with silver fluoride yields 3β-hydroxy-16α-fluoroandrost-5-en-17-one, 2a.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C1C=CC=CC=1>[C:17]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cnc(CO)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cnc(COC(=O)C(C)(C)C)cn1
Reaction time: 7 h
Yield: 71.5 %

Procedure:
To a solution of 2-hydroxymethyl-5-methylpyrazine (6.2 g) and triethylamine (6.4 ml) in anhydrous benzene (150 ml) dropwise addition was made of a solution of pivaloyl chloride (6.15 ml) in anhydrous benzene (50 ml). The solution was maintained at boiling for 7 hours, the solvent was then evaporated and the residue treated with acetone. After filtration of the insoluble solid, the filtrate was evaporated to dryness and the residue re-dissolved in chloroform. The chloroform solution was first dehydrated and then evaporated to dryness, obtaining 7 g (71.5%) of 5-methyl-2-pyrazinylmethyl pivalate, b.p.=74° C./0.1 mmHg.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[N:13][C:12]=2[N:22]2[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]2)[CH2:5][CH2:4]1>[Ni].C1COCC1>[F:34][C:2]([F:1])([F:33])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[N:13][C:12]=2[N:22]2[CH2:23][CH2:24][CH:25]([C:28]([F:30])([F:31])[F:29])[CH2:26][CH2:27]2)[CH2:5][CH2:4]1
Reactant: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reaction time: 4 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-5-nitro-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid amide (120 mg, 0.24 mmol), Ra—Ni (30 mg) and THF (20 mL) is stirred under 50 psi H2-atmosphere for 4 h. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: Cl[CH:2]1[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1.C(N(CC)CC)C.NC1N=CN=C([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)C=1>C(O)CCC>[O:6]=[S:4]1(=[O:7])[CH2:5][CH:2]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: O=S1(=O)CC(Cl)C1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(C2CS(=O)(=O)C2)CC1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
3-Chlorothietane 1,1-dioxide 50-1 (0.50 g, 3.56 mmol) was dissolved in n-butanol (4 mL) then triethylamine (1.08 g, 10.67 mmol) was added followed by tert-butyl piperazine-1-carboxylate 12-1 (0.66 g, 3.56 mmol). This was then stirred at 150° C. for 5 hours. Upon cooling the solid was filtered off, washed with n-butanol, ethyl ether and then purified on a silica column to afford 50-2. 1H-NMR (CDCl3): 4.10(complex, 4H); 3.46(t, 4H); 3.19(m, 1H); 2.36(t, 4H); 1.46(s, 9H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:4].C([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]2[C:48]3[C:43](=[CH:44][C:45]([C:49](O)=[O:50])=[CH:46][CH:47]=3)[C:42]([CH3:52])=[C:41]2[CH3:53])=[CH:35][CH:34]=1)=[O:26])(C)(C)C>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C@@H:3]([NH:2][C:49]([C:45]1[CH:44]=[C:43]2[C:48](=[CH:47][CH:46]=1)[N:40]([CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:28]3[C:27]([C:25]([OH:26])=[O:24])=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:38][CH:37]=1)[C:41]([CH3:53])=[C:42]2[CH3:52])=[O:50])[CH3:4])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)[C@@H]3CCCN3C(=O)OCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-benzyl 2-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 630 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:33].CO>C(Cl)Cl>[NH2:33][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CC1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)C3CC3)c2F)n1
Temperature: 80 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide (125 mg, 0.252 mmol) and 7M ammonia in MeOH (7 mL, 0.49 mmol) was heated in a sealed tube to 80° C. for 2 days. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were concentrated to yield the crude product as a yellow solid (62 mg). The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA in both). The combined clean fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound was obtained as a yellow solid (26 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 7.86 (d, J=5.4 Hz, 1H), 7.49 (td, J=7.4, 2.2 Hz, 1H), 7.11-7.38 (m, 2H), 6.53 (s, 2H), 5.84 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.43 (t, J=4.7 Hz, 4H), 2.53-2.68 (m, 1H), 0.74-0.92 (m, 4H). MS (ESI): 477.0 [M+H]+.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[Si:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[CH:19]=[CH:20][C:15]=1[C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h

Procedure:
To a flask equipped with magnetic stirrer was added cis-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine (700 mg, 1.33 mmol) and ethanol (30 ml). To the stirred solution was added palladium (10% w/w on activated carbon, 283 mg, 0.27 mmol) as a slurry in ethanol (5 ml). The reaction vessel was evacuated then placed under hydrogen. The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 18 hr then filtered through a celite plug, washing with methanol (100 ml). The solvent was removed in vacuo affording the title compound (561 mg, 97%) as a colourless oil. δH(CDCl3) 0.01 (6H, s), 0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s), 1.21-1.55 (10H, m), 2.64 (1H, m), 3.05 (1H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.84 (1H, d).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.[CH:13]1([O:16][CH2:17][CH2:18][OH:19])[CH2:15][CH2:14]1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1>>[Cl:12][C:8]1[C:9]([O:29][C:27]2[CH:26]=[CH:25][C:24]3[B:20]([OH:30])[O:21][CH2:22][C:23]=3[CH:28]=2)=[N:10][C:2]([O:19][CH2:18][CH2:17][O:16][CH:13]2[CH2:15][CH2:14]2)=[C:3]([CH:7]=1)[C:4]#[N:6]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Reactant: OCCOC1CC1
Reactant: OB1OCc2cc(O)ccc21
Product: N#Cc1cc(Cl)c(Oc2ccc3c(c2)COB3O)nc1OCCOC1CC1

Procedure:
This compound was prepared from 2,5,6-trichloronicotinamide, 2-cyclopropoxyethanol, and benzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 0.35-0.4 (m, 4H), 3.2-3.32 (m, 1H), 3.55-3.62 (m, 3H), 4.1-4.12 (m, 2H), 5.0 (s, 2H), 7.24 (dd, J=6.0, 1.4 Hz, 1H), 7.33 (s, 1H), 7.8 (d, J=6.7 Hz, 1H), 8.6 (s, 1H), 9.26 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.247 g, 1.02 mmol), 2-chloro-3-nitropyridine (0.325 g, 2.05 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were combined in dry DMF (0.15 mL). The solution was refluxed 4 hours then 0.5 mL more DMF was added and the mixture was allowed to stir at ambient temperature overnight. 2-Chloro-3-nitropyridine (0.105 g, 0.69 mmol), and 4-dimethylaminopyridine (0.062 g, 0.51 mmol) were added and the mixture was refluxed 2 hours more. The solvent was removed in vacuo and the residue was taken up in methylene chloride. This organic phase was washed with 0.5N sodium hydroxide and brine; then it was dried over calcium sulfate and concentrated to a red oil which was flash chromatographed on silica gel (1×4 inches). Gradient elution with 50% to 75% ethyl acetate/hexane followed by elution with 100% ethyl acetate gave a dark colored oil which crystallized upon addition of ether (2 mL) to yield 0.19 g (51%) as a dark red solid: mp 127.5°-129° C. Analysis calculated for C20H21N5O2 ; C, 66.10; H, 5.82; N, 19.27. Found: C, 66.04; H, 5.81; N, 19.02.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
2-Bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate (24 g, 70.0 mmol) obtained in Step 4 was placed into a flask and dissolved in MeOH (350 mL). The solution was charged with K2CO3(11.64 g, 1.2 eq) and stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with a brine solution. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (19.5 g, 93%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=2)[CH2:17][CH2:18]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc2[nH]cc(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Sodium hydride (115 mg, 4.8 mmol) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine (1.5 g, 4.17 mmol) [prepared as described in Step 1 above] in dimethylformamide (12 ml) at 0° C. After 30 min., methanesulfonyl chloride (0.81 ml, 10.43 mmol) was added and after stirring for 2.5 h the reaction mixture was allowed to warm to RT over 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water, brine and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (54%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Fc1cccc(CBr)c1F
Product: O=Cc1cccc2c1ccn2Cc1cccc(F)c1F
Yield: 77.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 580 mg of indole-4-carbaldehyde and 911 mg of 2,3-difluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 841 mg of 1-(2,3-difluorobenzyl)indole-4-carbaldehyde as pale brown crystals. The yield thereof was found to be 76%.
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH:19]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[NH2:30])=[O:24])([CH3:21])[CH3:20]>CC(N(C)C)=O>[CH:19]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[NH:30][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)=[O:24])([CH3:21])[CH3:20]
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)NC(=O)[C@H]1CCC[C@H]1N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Cl)nc1N[C@@H]1CCC[C@@H]1C(=O)NC(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1 g (6.1 mmol, 1 eq) 5-methyl-2,4-dichloropyrimidine (prepared analogously to A-1a) are dissolved in 3 mL DMA and then 5.3 mL (30.5 mmol, 5 eq) Hünig base are added dropwise. 1.03 g (6.1 mmol, 1 eq) (1S,2R)-2-aminocyclopentanecarboxylic acid isopropylamide are added and the reaction mixture is stirred for 1 h at 70° C. HPLC monitoring shows that the reaction is total and only one regioisomer is formed. The reaction mixture is combined with RP gel, the volatile constituents are eliminated in vacuo, the product is purified by column chromatography through an RP phase and isolated (from water/MeCN (+0.2% HCOOH in each case) from 82/18 to 60/40 in 15 min). Corresponding product fractions are combined, freed from the solvent by freeze-drying and 956 mg of C-1d are obtained.