Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])=[CH:12][C:13]=1[C:14]#[C:15][CH2:16][C:17]([OH:40])([C:36]([F:39])([F:38])[F:37])[CH2:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](=[O:35])(=[O:34])[N:29]=CN(C)C)([CH3:21])[CH3:20])(C)(C)C.C1CCN2C(=NCCC2)CC1.O>CO>[CH2:44]([S:41]([C:11]1[CH:12]=[C:13]2[CH:14]=[C:15]([CH2:16][C:17]([OH:40])([C:36]([F:39])([F:37])[F:38])[CH2:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH2:29])(=[O:35])=[O:34])([CH3:21])[CH3:20])[NH:7][C:8]2=[CH:9][N:10]=1)(=[O:42])=[O:43])[CH3:45]
Reactant: CCS(=O)(=O)c1cc(C#CCC(O)(CC(C)(C)c2ccccc2S(=O)(=O)N=CN(C)C)C(F)(F)F)c(NC(=O)OC(C)(C)C)cn1
Solvent: O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)c1cc2cc(CC(O)(CC(C)(C)c3ccccc3S(N)(=O)=O)C(F)(F)F)[nH]c2cn1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 48.2 %

Procedure:
To a vial was added {4-[6-(2-{[1-dimethylaminomethylidene]sulfamoyl}phenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-6-ethanesulfonylpyridin-3-yl}carbamic acid tert-butyl ester (48 mg, 0.07 mmol) in 3 mL of methanol, followed by the addition of DBU (106 mg, 0.7 mmol). The reaction mixture was stirred at 70° C. for 90 minutes. To the reaction was added 0.5 mL of water, and the reaction mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with 0-5% MeOH/CH2Cl2 to afford 18 mg (48%) of 2-[3-(5-ethanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]benzenesulfonamide. MS (ES+) m/z 534 [M+H]+.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:15]([Cl:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)Cl
Reactant: CCCCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCN(C(=O)Cl)c1ccccc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 4.05 g (24.8 mmole) of N-pentylaniline (from Step A) in 45 ml of toluene and 8.96 ml (24.8 mmole) of 2.77N NaOH were mechanically stirred at -5° C., and 25.7 ml (49.6 mmole) of 1.93M phosgene in toluene was added dropwise over 30 minutes while maintaining -5°. After half the phosgene solution had been added, the rate of addition was increased easily. After stirring at -5° for an additional 30 minutes, the phases were separated and the toluene layer was dried over 10 g of solid sodium chloride. Concentration gave 5.5 g (98%) of dark yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:33][CH:34]([Cl:38])[C:35]([NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:36]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2C(NC(=O)C(Cl)Cl)C(=O)N12
Yield: 80.6 %

Procedure:
7-Amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (6.61 g) was suspended in methylene chloride (60 ml) and bis(trimethylsilyl)acetamide was added to the suspension to give a solution. A solution of dichloroacetyl chloride (3.24 g) in methylene chloride (10 ml) was added to the solution obtained above at -20° C under stirring. The mixture was stirred at the same temperature for 20 minutes. Methylene chloride was distilled off under reduced pressure after addition of a little water. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried, and the solvent was distilled off under reduced pressure. The residue was pulverized by treating with ether and precipitates were collected by filtration to give 7-dichloroacetamido-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (7.12 g).
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15]2[C:14](=[O:22])[NH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].C1C(=O)N([I:30])C(=O)C1.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[I:30][C:11]1[C:10]2[N:9]=[C:8]([NH:7][CH:2]([CH3:1])[C:3]([CH3:5])([CH3:6])[CH3:4])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:16]=3[C:15]=2[C:14](=[O:22])[NH:13][CH:12]=1
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cnccc12)C(C)(C)C
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cnccc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[(1,2,2-trimethylpropyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one (221 mg, 0.746 mmol) in acetic acid (7.5 mL), NIS (336 mg, 1.491 mmol) was added. After stirring for 2 h at room temperature, aqueous sodium hydrogen carbonate was added, and then aqueous sodium thiosulfate pentahydrate (5%) was added. The aqueous mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 4-iodo-6-[(1,2,2-trimethylpropyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one as an orange solid. 1H NMR (500 MHz, C2D6SO) δ 11.58 (d, 1H), 11.00 (s, 1H), 8.74 (s, 1H), 8.47 (d, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 4.93 (m, 1H), 1.23 (d, 3H), 0.99 (s, 9H). LRMS (ESI) calc'd for (C17H19IN4O) [M+H]+, 423.1; found 423.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC(O)c1cccc(F)c1F
Agent: [Pd]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCCCCCCc1cccc(F)c1F

Procedure:
Quantities: compound from Example 21 (56.4 g, 0.21 mol), phosphorus pentoxide (74.5 g, 0.53 mol) and 5% palladium-on-charcoal (4.58). The experimental procedure was as described in Example 22.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)#[N:2].[OH-].[K+].OO.CC[O:36]CC>CC(C)=O>[C:1]([CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)(=[O:36])[NH2:2]
Reactant: CCOCC
Reactant: N#CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-(2-Cyanoethyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in acetone and treated with aqueous KOH. Hydrogen peroxide was added in portions over seven days at ambient temperature. Extractive work-up and trituration with ether gave 4-(2-carbamoylethyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.58 (m, 4H); 5.3 (br s, 1H; 6.0 (br s, 1H); 6.26 (s, 1H); 7.0-7.35 (m, 15H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.[CH2:17]([OH:21])[CH2:18][C:19]#[CH:20].P.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Pd].[Cu]I>[OH:21][CH2:17][CH2:18][C:19]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:4][C:3]=2[CH:20]=1
Reactant: N#Cc1ccc(-c2ccc(O)c(I)c2)cc1
Reactant: C#CCCO
Agent: [Cu]I
Agent: [Pd]
Agent: P
Solvent: CC(=O)OC(C)C
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1

Procedure:
treating 4′-hydroxy-3′-iodo-1,1′-biphenyl-4-carbonitrile with 3-butyn-1-ol, a palladium source with a phosphine for the palladium and a metal halide in the presence of a base, for example using palladium(ll) acetate, triphenylphosphine, copper(I) iodide in the presence of diisopropylamine, in isopropyl acetate to provide 4-[2-(2-hydroxyethyl)-1-benzofuran-5-yl]benzonitrile;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](Cl)=[O:26])=[CH:24][C:19]=2[CH2:18][CH2:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:25]([C:23]4[CH:22]=[CH:21][C:20]5[O:16][CH2:17][CH2:18][C:19]=5[CH:24]=4)=[O:26])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc2c(c1)CCO2

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,3-dihydro-1-benzofuran-5-carbonyl chloride (68 mg; 0.37 mmol; 1.5 eq.) as a white solid (25.7 mg, 29%). HPLC, Rt: 3.14 min. (purity 78.8%). LC/MS, M+(ESI): 347.4, M−(ESI): 345.3.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=1[C:21]#[N:22]>>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1c(N)cccc1F
Reactant: O=C(NC1CCC(CO)CC1)c1ccncc1
Product: N#Cc1c(N)cccc1OCC1CCC(NC(=O)c2ccncc2)CC1

Procedure:
Prepared as in Example 22b from N-(4-(Hydroxymethyl)cyclohexyl)isonicotinamide (Example 108c) and 2-amino-6-fluorobenzonitrile as a colorless oil (6%). MS 351 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[C:22]5[C:27]=4[CH2:26][C:25](=[O:28])[CH2:24][CH2:23]5)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][C:15]([NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[C:22]5[C:27]=4[CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]5)=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2cccc(Nc3ncc(-c4ccc(N5CCCC5)cc4)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(-c4ccc(N5CCCC5)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 7C for the product of Example 1I. 1H NMR (DMSO-d6) δ 8.86 (s, 1H), 7.61 (d, 2H, J=7.2 Hz), 7.37 (d, 1H, J=8.9 Hz), 7.07 (t, 1H, J=7.8 Hz), 7.02 (s, 1H), 6.80 (d, 1H, J=8.2 Hz), 6.57 (d, 2H, J=8.8 Hz), 4.79 (d, 1H, J=4.1 Hz), 3.91 (m, 1H), 3.25 (m, 4H), 2.66-2.97 (m, 4H), 1.99 (m, 4H), 1.89 (m, 1H), 1.62 (m, 1H); MS (ESI+) m/z 376 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[N:27][N:26]=[C:25]1[C:39]12[CH2:46][CH2:45][C:42]([C:47]([NH:49][NH2:50])=[O:48])([CH2:43][CH2:44]1)[CH2:41][CH2:40]2>CN(C=O)C>[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:36])([F:38])[F:37])=[N:27][N:26]=[C:25]1[C:39]12[CH2:46][CH2:45][C:42]([C:47]([NH:49][NH:50][C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][C:7]([F:10])([F:9])[F:8])=[O:48])([CH2:41][CH2:40]1)[CH2:43][CH2:44]2
Reactant: CC(CC(F)(F)F)C(=O)O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)NN)(CC1)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(CC(F)(F)F)C(=O)NNC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Reaction time: 0.5 h

Procedure:
A solution of 2-methyl-4,4,4-trifluorobutyric acid (108 mg, 0.692 mmol) and 1,1′-carbonyldiimidazole (101 mg, 0.623 mmol) in DMF (1 ml) was stirred at room temperature under a nitrogen atmosphere. After 30 min, compound 13-A (100 mg, 0.254 mmol) was added and the solution stirred overnight. DMF was removed in vacuo and the solid was redissolved in CH3CN (4 ml). Product was purified by Gilson reverse phase chromatography eluting with a 10-90% CH3CN (0.1% TFA)/water (0.1% TFA) gradient. Solvent was removed in vacuo and the product free based from methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and the solvent removed to yield 13-B as a white solid. MS (ESI+)=532.18 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:5]([NH:14][C:15]([C:17]2[N:21]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=3)[N:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:18]=2)=[O:16])=[C:4]([CH3:33])[CH:3]=1.[CH:34](=O)/[CH:35]=[CH:36]/[CH3:37].N>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH:11]([NH:10][C:8]([C:6]1[C:7]2[CH:34]=[CH:35][C:36]([CH3:37])=[N:1][C:2]=2[CH:3]=[C:4]([CH3:33])[C:5]=1[NH:14][C:15]([C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:18]=1)=[O:16])=[O:9])([CH3:13])[CH3:12]
Reactant: Cc1cc(N)cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: C/C=C/C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(C(=O)NC(C)C)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(C)cc2n1
Temperature: 25 °C

Procedure:
1.70 g (3.53 mMol) N-(4-amino-2-methyl-6-(((1-methylethyl)amino)carbonyl)phenyl)-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (known from WO 03/016284) and 41 mg (0.18 mmol) benzyltriethylammonium chloride in 35 mL conc. HCl and 35 mL toluene are vigorously stirred at 60° C. Then 0.58 mL (7 mmol) crotonaldehyde is added and the reaction mixture is stirred under reflux during 1 hour. The mixture is then cooled to ambient temperature, diluted with 10 mL ethyl acetate/tetrahydrofuran (1:1, v/v) and neutralised with an aqueous solution of concentrated ammonia. The organic phase is extracted and washed once with brine, then dried on Na2SO4, filtrated and evaporated. After column chromatography purification on silica gel with dichloromethane/tetrahydrofuran (3:1) as eluents, the compound is recrystallised from tetrahydrofuran/hexane to afford a colourless solid; LC/MS:531/533 (M+H)+, m.p.: >240° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][CH:28]1[C:40](=[O:41])[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH2:30][CH2:29]1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:21][C:22]1[N:26]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[N:24][C:23]=1[CH2:27][CH:28]1[C:40](=[O:41])[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH2:30][CH2:29]1
Reactant: Cc1[nH]cnc1CC1CCc2[nH]c3ccccc3c2C1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 137.7 %

Procedure:
A solution of triphenylchloromethane (4.2 g) in dry DMF (40 ml) was added dropwise to a solution of 1,2,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one (3.5 g) and triethylamine (1.75 ml) in dry DMF (35 ml) under nitrogen. After stirring for 4 h the mixture was poured into water (300 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (200 ml), dried and evaporated to give an oil (ca. 9 g) which was purified by FCC eluting with System A (200:10:1) to give the title compound (4.57 g) as a foam, t.l.c. (System A 200:10:1) Rf 0.32.
Reaction SMILES: [C:1]([O:6][CH:7]1[C:10]([CH3:12])([CH3:11])[CH:9]([OH:13])[C:8]1([CH3:15])[CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:21]=[C:17]([CH3:16])[CH2:18][C:19]([O:13][CH:9]1[C:10]([CH3:12])([CH3:11])[CH:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[C:8]1([CH3:15])[CH3:14])=[O:20]
Reactant: C=C1CC(=O)O1
Reactant: C=C(C)C(=O)OC1C(C)(C)C(O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OC1C(C)(C)C(OC(=O)CC(C)=O)C1(C)C
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
To a 3-L flask was charged 2,2,4,4-tetramethylcyclobutane-1,3-diol (423.26 g, 3.0 moles), THF (550 g), DMAP (0.5 g) and N-diphenylnitrosoamine (2 g) and methacrylic anhydride (308 g, 2 moles). Mixture heated to reflux (81° C.) and held for six hours. Reaction cooled and THF removed with a rotary evaporated. To the crude residue was added heptane (1200 mL) and cooled to 0-5° C. for 30 minutes. The precipitated unreacted starting material was filtered off and the cake washed with cold heptanes (600 mL). Heptane removed from filtrate with rotary evaporator and the crude product distilled through a 12×1 inch Penn State packed column to produce 3-hydroxy-2,2,4,4-tetramethylcyclobutyl methacrylate in 97.3% NMR assay. To a 500 mL flask was charged 3-hydroxy-2,2,4,4-tetramethylcyclobutyl methacrylate (32 g, 0.151 moles), methylene chloride (75 g), DMAP (0.04 g) and the mixture cooled to 0-5° C. To this was added dropwise over one hour freshly distilled diketene (12.7 g) dissolved in methylene chloride (20 g). After addition, the reaction was allowed to warm to room temperature and stir overnight. Once reaction was complete, the dichloromethane was removed at 60° C. with house vacuum. Crude product distilled via Kugelrohr distillation to provide desired product of 94.8% GC assay.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:24]#[N:25]>CO>[C:24]([C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:25]
Reactant: Clc1c2ccccc2nc2cc3ccccc3cc12
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: N#Cc1c2ccccc2nc2cc3ccccc3cc12
Temperature: 160 °C
Reaction time: 4.5 h
Yield: 136.7 %

Procedure:
A mixture of 12-chloro-benz[b]acridine (2.3 g, 8.68 mmol), potassium cyanide (620 mg, 9.55 mmol) and copper(I) cyanide (391 mg, 4.43 mmol) in anhydrous methanol (16 ml) was bubbled with nitrogen for 1 minute and then kept in a sealed tube. The mixture was heated at 160° C. with stirring for 4.5 hours and cooled. The red-brown mixture was evaporated and the residue was flash-chromatographed (W.C. still et al: J. Org. Chem., 43, 2923, (1978)) on a silica column (Baker silica gel, Cat# 7024-1) packed with hexane and eluted with 10% ethyl acetate-hexane, yielding red 12-cyano-benz[b]acridine (1.54 g, 70%). Rf 0.7 (silica gel, hexane/ethyl acetate 2:1). MS (FAB, Thioglycerol Matrix): m/z 255 (M+1).
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[CH:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.CCOC(C)=O>[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH:72][C:17]([C:6]3[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=3)=[O:19])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[CH:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (3.34 g, 10.9 mmol) (as prepared in Example 3, step (d)) in 20 mL DCM was added DIEA (3.8 mL, 21.8 mmol) and PyBroP (5.6 g, 12.0 mmol), and the reaction stirred at 25° C. for 15 min. A solution of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 10.9 mmol) (as prepared in Example 13, step (d)) in 10 mL DCM was added and the reaction stirred for 8 h at 25° C. The reaction was diluted EtOAc (60 mL) and washed with NaHCO3 (2×60 mL) and brine (100 mL) and the organic layer was dried over Na2SO4 and then concentrated. The title compound was purified by flash chromatography (silica gel, 2% EtOAc/DCM) to give 5.5 g (85%) of the title compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C33H47N5O4Si, 606.2 (M+H), found 606.2.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)C>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCC(CO)CO
Reaction time: 15 h
Yield: 6 %

Procedure:
In anhydrous diethyl ether was dissolved 100 g of the obtained diethyl heptylmalonate, and the mixture was added dropwise to a solution of 28.7 g of lithium aluminum hydride dispersed in 270 ml of diethyl ether. The mixture was stirred for 15 hours. Then, to the reaction mixture was added gradually 3N hydrochloric acid to make excess lithium aluminum hydride inactive. After washing with 10% aqueous solution of sodium carbonate, then water, the resulting ether layer dried with anhydrous magnesium sulfate. After distilling ether under reduced pressure, the residue was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate=4/1) and distilled under reduced pressure to give 41.2 of 2-heptyl-1,3-propanediol (yield: 6%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:15][C:16](O)=[O:17])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[C:7]1([CH2:15][CH2:16][OH:17])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=1
Reactant: O=C(O)CC1=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1=Cc2ccccc21
Reaction time: 8 h
Yield: 85 %

Procedure:
A three-necked flask is charged under a stream of nitrogen with 7.4 g of lithium aluminium hydride, and 70 ml of anhydrous tetrahydrofuran are then added. A solution of 2-benzocyclobuten-1-ylacetic acid (prepared according to the process described in J. Org. Chem., (1979), 44, p. 1036) in 120 ml of tetrahydrofuran is then introduced dropwise. The reaction solution is left stirring overnight. The flask is then cooled with an ice bath and the mixture is hydrolyzed by adding 6.6 ml of water, 6.6 ml of 4N sodium hydroxide and then 19.8 ml of water very gently. The complex is drained and washed with ethyl ether and the organic phase is dried over magnesium sulfate. After filtration, the filtrate is evaporated to dryness to obtain the expected compound.