Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:20])([OH:19])[C:14](OCC)=[O:15])=[CH:9][CH:8]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].[C:39]1([NH:45][NH2:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)C>C(Cl)Cl.C(OCC)C>[CH3:20][C:13]1([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=3[Si:2]([CH3:1])([CH3:26])[CH3:25])=[CH:12][CH:11]=2)[O:19][C:27](=[O:28])[N:46]([NH:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:14]1=[O:15]
Reactant: CCOC(=O)C(C)(O)c1ccc(OCc2ccccc2[Si](C)(C)C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(c2ccc(OCc3ccccc3[Si](C)(C)C)cc2)OC(=O)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of ethyl 2-(4-(2-trimethylsilylbenzyloxy)phenyl)lactate (0.93 g, 2.5 mmol) in CH2Cl2 (15 mL) was treated with 1,1'-carbonyldiimidazole (0.53 g, 3.3 mmol) and the resulting mixture was heated overnight. The resulting solution was diluted with diethyl ether (45 mL) and washed with H2O (two-times with 15 mL), brine (15 mL), dried (MgSO4) and concentrated under vacuum. The residue was dissolved in CH2Cl2 and to the solution was added PhNHNH2 (0.46 g, 4.3 mmol) and acetic acid (0.24 mL, 4.3 mmol). The resulting mixture was stirred at room temperature for 60 h afterwhich time the mixture was diluted with CH2Cl2 (20 ml) and washed with 1N aqueous HCl (10 mL) and H2O (10 mL). The organic phases were dried (MgSO4) and concentrated under vacuum to yield a residue which was subjected to column chromatography (75 g SiO2 eluted with 2:2:6 diethyl ether/CH2Cl2 /hexanes) thereby affording the product of Step E as a yellow powder, 0.62 g; (54%); m.p. 112°-114° C.; IR (mineral oil): 3308, 1738, 1245 cm-1 ; 1 H NMR (CDCl3): δ7.6 (d,1H), 7.55 (d,2H), 7.5 (d,1H), 7.45 (t,1H), 7.35 (t,1H), 7.25 (m,2h), 7.0 (d,3H), 6.75 (d,2H), 6.05 (s,1H), 5.1 (s,2h), 2.0 (s,3H), 1.23 (t,3H), 0.3 (s,9H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:28])[C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCCC3=O)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 328.9 %

Procedure:
5,6-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 5b) (0.15 g, 0.036 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.8 mL, 0.88 mmol, 1M solution in THF) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.05 ml, 0.88 mmol) was added slowly, and the reaction mixture was slowly, warmed to room temperature and stirred for 4 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material obtained was purified by column chromatography using [EtOAc-hexane (1:9) as eluant] to afford the title compound (0.05 g, 32%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.54 (d, J=9 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 3.55-3.49 (m, 1H), 3.22-3.15 (m, 1H), 2.68-2.64 (m, 1H), 2.42 (s, 3H), 2.27-2.22 (m, 1H), 1.95-1.87 (m, 1H), 1.25-1.17 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1nc[nH]n1
Reactant: BrCc1ccccc1
Product: Nc1ncn(Cc2ccccc2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and benzyl bromide. The title compound was obtained as a colorless solid (Yield=14%). MS ISP (m/e): 175.3 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:19][C:20]1[CH:66]=[CH:65][C:23]([CH2:24][N:25]([CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:26][C:27]([C@:29]23[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]2[C@@H:31]2[C@@:44]([CH3:47])([CH2:45][CH2:46]3)[C@@:43]3([CH3:48])[C@@H:34]([C@:35]4([CH3:52])[C@@H:40]([CH2:41][CH2:42]3)[C:39]([CH3:50])([CH3:49])[C@@H:38](O)[CH2:37][CH2:36]4)[CH2:33][CH2:32]2)=[O:28])=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:12][C:7]([CH3:13])([CH2:8][C:9]([O:11][C@H:38]1[CH2:37][CH2:36][C@@:35]2([CH3:52])[C@@H:40]([CH2:41][CH2:42][C@:43]3([CH3:48])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:44]3([CH3:47])[CH2:45][CH2:46][C@@:29]3([C:27](=[O:28])[CH2:26][N:25]([CH2:24][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:66][CH:65]=4)[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]32)[C:39]1([CH3:49])[CH3:50])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (11.91 g, 58.9 mmol), N,N-dimethylpyridin-4-amine (4.50 g, 36.8 mmol) in DCM (20 mL) was added EDC (11.29 g, 58.9 mmol). The reaction mixture was stirred at rt for 1 h. Then, (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (52) (5 g, 7.36 mmol) was add. Upon completion, the mixture was washed with 2 M HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The product was purified by a silica gel column using dichloromethane/methanol (20:1) to afford 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (53) (1.8 g, 1.917 mmol, 26.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.27 (s, 4H), 4.60-4.39 (m, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.59 (d, J=13.8 Hz, 1H), 3.50-3.05 (m, 3H), 2.82-2.63 (m, 2H), 2.63-0.53 (m, 67H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CO[CH:35](OC)[N:36](C)[CH3:37]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:25]([N:24]=[CH:16][N:36]([CH3:37])[CH3:35])=[S:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C=NC(=S)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 17.7 g (82.6 mmol) 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) in 150 ml THF was treated with 11.1 ml (82.6 mmol) benzoyl isothiocyanate and stirred for 1 h at room temperature. After evaporation of the solvents the residue was taken up in 100 ml MeOH and treated with 34.2 g (248 mmol) potassium carbonate in 100 ml water. After stirring the mixture for 16 h at room temperature all volatiles were removed and the residue extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 solution and dried with MgSO4. After evaporation of the volatiles 88.1 ml (661 mmol) N,N-dimethylformamide dimethyl acetal was added and the mixture was heated to 110° C. for 16 h. The precipitate was filtered off, washed with n-hexane and dried to yield 21.5 g (79%) of the title compound as pink amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[C@H:47]([NH2:49])[CH3:48]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:49][C@@H:47]([C:43]2[S:42][CH:46]=[CH:45][N:44]=2)[CH3:48])=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C[C@@H](N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4nccs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (28 mg, yield 62%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1F)[C:24]([O:26][CH3:27])=[O:25]>>[F:20][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:28]=[CH:29][C:30]=1[N:10]1[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Potassium carbonate (5.56 g, 40.3 mmol) and tert-butyl piperazine-1-carboxylate (6.92 g, 37.2 mmol) were combined, methyl 3,4-difluorobenzoate (5.33 g, 31.0 mmol) was added and the reaction mixture was stirred at 90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered. This was concentrated down to about 5-10 mL and subjected to flash column chromatography on silica gel (120 g SiO2, hexanes: ethyl acetate 1:0 to 4:1) to afford tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.702 g, 13.90 mmol, 44.9% yield) as a white solid. ESI-MS: m/z 339 (M+H)+.
Reaction SMILES: FC(F)(OC1C=CC(C(F)(F)F)=CC=1)C(F)(F)F.S(=O)(=O)(O)O.ClS(O)(=O)=O.[F:29][C:30]([F:45])([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)[C:31]([F:34])([F:33])[F:32].S(Cl)([Cl:48])=O>CN(C)C=O>[F:29][C:30]([F:45])([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([Cl:48])=[O:41])=[CH:38][CH:37]=1)[C:31]([F:34])([F:33])[F:32]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(OC(F)(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 115 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7.5 parts of p-pentafluoroethoxy benzotrifluoride, 118 parts of 98% sulfuric acid, 11 parts of chlorosulfonic acid (HSO3Cl) and 2 parts of silica gel was heated to 115° C. and maintained thereat for 1.5 hours, then cooled and poured over ice. The resultant crude p-pentafluoroethoxy benzoic acid solid was mixed with 1 part of dimethyl formamide and 25 parts of thionyl chloride. The mixture was stirred for about 45 minutes and an additional 67 parts of thionyl chloride was added. The reaction mixture was then heated at reflux for 2 hours and the product distilled to yield 3.4 parts of p-pentafluoroethoxy benzoyl chloride (b.p. 152° C.-157° C.). ##STR15##
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=2[CH:18]=1)#[CH:13].BrC1C=CC(S(NC2CCC3CC2C3(C)C)(=O)=O)=CC=1.C(O)CC#C>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:13]#[C:12][C:14]2[O:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=3[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#Cc1cc2ccc(OC)cc2o1
Agent: C#CCCO
Agent: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Product: COc1ccc2cc(C#Cc3ccc(OC(C)=O)cc3)oc2c1
Yield: 56 %

Procedure:
When 4-iodophenyl acetate and 2-ethynyl-6-methoxybenzofuran were substituted for 4-bromo-N-(6,6-dimethylbicyclo [3.1.1]heptan-2-yl)benzene sulphonamide and but-3-yn-1-ol respectively in Example 18, Step B, the similar process afforded the title compound in 56% yield, as creamy paste. 1H-NMR (CDCl3) 7.56 (d, 2H, J=8.67 Hz); 7.41 (d, 1H, J=8.58 Hz); 7.10 (d, 2H, J=8.7 Hz); 6.97 (d, 1H, J=1.92 Hz); 6.9 (s, 1H); 6.88 (bd, 1H, J=8.61 Hz); 3.85 (5, 3H); 2.3 (s, 3H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].I[CH2:25][CH3:26]>O>[CH2:25]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)[CH3:26]
Reactant: O=C1Nc2ccccc2Nc2ncccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ccccc2NC(=O)c2cccnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 15 g of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 150 ml DMF was heated to 50° C. To the slurry was added 7.5 g (2 equiv) of 50% sodium hydride in mineral oil dispersion, during which time the temperature rose to 65° C. The mixture was cooled to 40° C. and then 6.0 ml of iodoethane was added. The resulting mixture was stirred at room temperature overnight, then poured into 700 ml of water and extracted with 700 ml of ether. The ether phase was dried (MgSO4) and concentrated to dryness. The crude product was purified by column chromatography on basic alumina to yield 3.6 g (21% of theory) of 6,11-dihydro-11-ethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 210°-220° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH:38]1[CH2:41][O:40][CH2:39]1)[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:30])[CH:38]5[CH2:39][O:40][CH2:41]5)[CH2:33][CH2:34]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C1CCNCC1)C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4COC4)CC3)n(C)c2n1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (179 mg, 0.46 mmol), methyloxetan-3-ylpiperidin-4-ylamine (94 mg, 0.55 mmol) and 4 Å powdered molecular sieves (400 mg) in DCE (10 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 418 as a cream solid (93 mg, 37%). LCMS (Method I): RT 2.31 min [M+H]+ 546.4. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.67 (t, J=6.5 Hz, 2 H); 4.60 (t, J=6.6 Hz, 2 H); 4.34 (m, 4 H); 3.98-3.88 (m, 1 H); 3.89-3.82 (m, 7 H); 3.72 (s, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 2.94 (d, J=11.2 Hz, 2 H); 2.35-2.24 (m, 1 H); 2.21 (s, 3 H); 2.13 (t, J=11.2 Hz, 2 H); 1.64 (d, J=12.2 Hz, 2 H); 1.54 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C(O[C:4](=[O:29])[C:5]([CH3:28])([CH3:27])[CH:6]([OH:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([CH3:25])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-:30].[K+].[NH2:32]O.CO.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C1COCC1>[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].[OH:26][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([CH3:25])[CH:16]=2)=[CH:9][CH:8]=1)[C:5]([CH3:27])([CH3:28])[C:4]([NH:32][OH:30])=[O:29]
Reactant: [OH-]
Reactant: CCOC(=O)C(C)(C)C(O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: NO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(O)C(C)(C)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A solution of 3-Hydroxy-2,2-dimethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.10 g, 0.25 mmol) in THF (1 mL) was treated with a solution of KOH/NH2OH/MeOH (3 mL) under nitrogen at room temperature. The reaction was stirred for 1.5 h, acidified with TFA and concentrated. The product was purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient to give the title compound (0.51 g, 54%) as a white solid. MS found: (M+H)+=381.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].CO.O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Temperature: 50 °C
Yield: 92.2 %

Procedure:
Methyl 3-methyl-4′-nitrobiphenyl-4-carboxylate (0.70 g, 2.1 mmol) was suspended in THF (5 mL), MeOH (5 mL) and water (2.5 mL), and NaOH (0.41 g, 10.3 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo and purified by reversed-phase HPLC to give 0.498 g (94%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.62-7.68 (m, 2H), 7.91-8.05 (m 3H), 7.18 (t, 1H), 8.31 (d, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
2-Fluoronitrobenzene (3.0 g) and 4-chloroaniline (2.5 g) were dissolved in pyridine (30 ml) and stirred at 80° C. for 18 hours. The resultant solution was allowed to cool, and thereafter, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from ethyl acetate-hexane, to thereby yield the target compound (2.5 g) as pale-brown crystals.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[BrH:21].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:1]([Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCCO
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Yield: 51 %

Procedure:
To nonadecanol (1.0 g, 3.5 mmol) was added 1500 μL hydrobromic acid (48% wt/vol). After cooling in ice, concentrated sulfuric acid (400 μL) was added and the reaction was allowed to warm to room temperature. A condenser and drying tube were placed over the reaction and the mixture was slowly heated to 120° C. The solution was kept at reflux for five hours and then cooled. The solidified product was resuspended in a mixture of ethyl acetate (50 mL) and water (10 mL). The aqueous layer was removed and the organic layer was washed with water (2×10 mL), then 5% sodium bicarbonate (10 mL) and then one final time with water. The resulting solution was dried over magnesium sulfate and filtered. The solvent was removed to provide a crude product which was purified by silica chromatography (hexanes:ethyl acetate, 80:20, as eluant) to give the desired 1-nonadecyl bromide (624 mg, 1.79 mmol, 51%). 1H NMR (CDCl3 , 300 MHz); δ3.40 (t, J=6.9 Hz, 2H), 1.83 (m, 2H), 1.41 (br s, 2H), 1.25 (s, 32H), 0.87 (t, J=6.7 Hz). 13C NMR (CDCl3' 67.93 MHz); δ33.94 32.83, 31.90, 29.65, 29.52, 29.42, 29.33, 28.75, 28.16, 22.66, 14.07. M.S. (EI+); 346 (M+), 267 (M-Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=CC3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[OH2:16].[C:17]([OH:20])(=O)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:17](=[O:20])[C:18]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CC(=O)O
Reactant: Clc1ccc2ccc3ccccc3c2c1
Reactant: O
Product: O=C1C(=O)c2ccc(Cl)cc2-c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 12.5 g (58.7 mmol) of 3-chlorophenanthrene from Step 3 in 350 mL of acetic acid was added 23.5 g (0.23 mol) of CrO3. The reaction was stirred 2 hrs at 100° C., cooled down to room temperature and poured into 2 L of water. The suspension was stirred 1 hr, filtered and washed with water. The residue was dried under high vacuum to afford 12.5 g (88%) of 3-chlorophenanthrene-9,10-dione.
Reaction SMILES: Cl.Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCC5CCN(CC)CC5)N=4)SC=3C=CC=2)=O)C[CH2:4]1.[CH:36]1([NH:39][C:40]([C:42]2[C:50]3[CH:49]=[C:48]([C:51]4[C:56]([Cl:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH2:61][CH:62]5[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]5)[N:52]=4)[S:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:38][CH2:37]1.ICC>>[ClH:24].[ClH:57].[CH:36]1([NH:39][C:40]([C:42]2[C:50]3[CH:49]=[C:48]([C:51]4[C:56]([Cl:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH2:61][CH:62]5[CH2:63][CH2:64][N:65]([CH2:3][CH3:4])[CH2:66][CH2:67]5)[N:52]=4)[S:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:37][CH2:38]1
Reactant: CCN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Agent: Cl
Solvent: CCI
Product: CCN1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-ethylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound may be prepared as the di-hydrochloride acid salt from 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and iodoethane. ES+(m/z) 498 (35Cl) and 500 (37Cl) [M(free base)+H].