Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[I-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH3:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:9]2[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[CH:20][CH2:21][CH3:22])[C:2]=2[CH3:1])=[O:18])=[CH:12][CH:13]=1
Reactant: Cc1c(C=O)cccc1C(=O)c1ccc(F)cc1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCC=Cc1cccc(C(=O)c2ccc(F)cc2)c1C

Procedure:
Using the procedure of Examples 1 and 2, 2-methyl-3-(p-fluorobenzoyl)-benzaldehyde and n-propyl-triphenyl phosphonium iodide were reacted to obtain 4-fluoro-3'-(butenyl)-2'-methyl-benzophenone which was hydrogenated to form 4-fluoro-3'-(n-butyl)-2'-methyl-benzophenone in the form of an oil.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]1[CH:12]2[CH:13]3C=CC([CH:11]2C=[CH:9]1)C3>>[CH2:5]([C:2]1([CH:3]=[O:4])[CH2:11][CH:12]2[CH2:13][CH:1]1[CH:9]=[CH:8]2)[CH2:6][CH3:7]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=C(C=O)CCC
Product: CCCC1(C=O)CC2C=CC1C2
Temperature: 170 °C
Yield: 44.9 %

Procedure:
A 5-L flask fitted with an overhead stirrer and a condenser was charged with di-n-butylamine (75 g) and acetic acid (70 g). Formaldehyde solution in water (1.3 L, 37%) was added and the resulting solution was heated to 50° C. with stirring. Pentanal (1 Kg) was then fed in over about 2 hours. After the feed was completed the temperature was maintained at 50° C. for 1 hour and then cooled to room temperature. The reaction mixture was poured into a separatory funnel. The organic layer was washed with water and purified by distillation to yield 2-methylene pentanal (820 g). 2-Methylene pentanal (302 g) and dicyclopentadiene (244 g) were loaded into a 2-L autoclave. The autoclave was sealed and heated to 170° C. The reaction was monitored by Gas Chromatography (“GC”) analysis, which showed the completion after 3 hours. The reaction was cooled to room temperature. The crude product was purified by distillation to yield 2-propylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (136 g). Product 2-methylene pentanal had the following NMR spectral characteristics:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:11])[NH:8]2)=[C:4]([Cl:12])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:23]#[N:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)C.O1CCOCC1>[Cl:12][C:4]1[N:3]=[C:2]([NH:1][C:26]2[CH:25]=[C:22]([CH:21]=[CH:20][C:27]=2[N+:28]([O-:30])=[O:29])[C:23]#[N:24])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:11])[NH:8]2
Reactant: Nc1nc(Cl)c2[nH]c(=O)[nH]c2n1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 46 %

Procedure:
To an oven-dried microwave flask under Ar was added 2-amino-6-chloro-7H-purin-8(9H)-one (0.64 g, 3.46 mmol, 1.0 equiv.) followed by anhydrous dioxane (10 mL) and anhydrous ethanol (4 mL); Cs2CO3 (Aldrich, 2.25 g, 6.92 mmol, 2 equiv.), 3-bromo-4-nitro-benzonitrile (1.02 g, 4.5 mmol, 1.3 equiv.), Xantphos (Strem, 0.6 g, 1.04 mmol, 0.3 equiv.) and Pd2(dba)3 (Strem, 0.32 g, 0.35 mmol, 0.1 equiv.) were all added as solids, and the mixture was stirred under Ar, at room temperature for 3 min. The flask was capped and heated in the microwave at 140° C. for 150 min (LC-MS shows reaction to be complete). The reaction mixture was cooled to room temperature, then concentrated in vacuo to give a dark brown residue, which was purified by flash chromatography (silica gel, gradual elution 3/1 ethyl acetate/hexanes, then 4/1 ethyl acetate/hexanes with 1% MeOH to 20% MeOH) to give the desired product as an orange solid in 46% yield. 1H NMR (300 MHz, CD3COOD) δ, ppm: 9.31 (d, 1H), 8.36 (d, 1H), 7.43 (dd, 1H); MS (EI) m/z 332.0 (MH)+.
Reaction SMILES: O[CH2:2][C:3]1([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[O:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:11]2[C:10]([C:9]3[O:23][CH2:2][C:3]4([CH2:4][CH2:5][CH2:6][CH2:7]4)[N:8]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:18]=1
Reactant: O=C(NC1(CO)CCCC1)c1cccnc1Oc1cccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1cncc(Oc2ncccc2C2=NC3(CCCC3)CO2)c1
Yield: 49.4 %

Procedure:
A solution of N-(1-Hydroxymethyl-cyclopentyl)-2-(pyridin-3-yloxy)-nicotinamide (0.045 grams, 0.144 mmole) and phosphorus oxychloride in toluene (5 ml) was stirred over night. The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate was added. The mixture was concentrated to give a crude product that was purified by chromatography on silica gel eluting with ethyl acetate to give a yellow oil (0.021 g). HRMS 296.1417; 1H NMR (400 mhz, CDCl3) d 1.65-1.74 (m, 4H), 1.86-1.91 (m, 2H), 1.96-2.03 (m, 2H), 4.25 (s, 2H), 7.08 (dd, J=7.5 Hz, 5.0 Hz, 1H), 7.32 (dd, J=8.3 Hz, 4.8 Hz, 1H), 7.51-7.54 (m, 1H), 8.15-8.22 (m, 2H), 8.43-8.50 (m, 2H).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1
Reactant: OB(O)c1ccncc1
Product: CCCCCCc1cccc(-c2nc(-c3ccncc3)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-[4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (example 45) was reacted with pyridin-4-yl-boronic acid to give the title compound as light yellow oil. MS: 530.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
7.65 g of N-t-butoxycarbonyl-L-serine and 3.88 g of 3,4-dihydro-2H-pyrane were dissolved in 60 ml of dichloromethane followed by the addition of 0.47 g of pyridinium p-toluene sulfonate and the solution was stirred for 3 hours at room temperature. After the reaction solution was washed with water and saturated brine, the solvent was distilled off under reduced pressure to obtain 9.90 g of the target compound. Yield: 92%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][Sn:9]([CH3:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1>>[CH3:8][Sn:9]([CH3:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: Brc1ccccn1
Agent: C[Sn](C)(C)c1ccccn1
Product: CCOC(=O)Cc1ccc(-c2ccccn2)cc1

Procedure:
The older known synthesis as described in EP 1244641 B1 on page 21 starts from 2-bromopyridine. In step 1 the 2-trimethylstannanylpyridine is prepared in a 45 to 50% yield (of the theory). The 2-trimethylstannanylpyridine is subsequently reacted with ethyl (4-bromophenyl)acetate in order to obtain the ethyl (4-pyridin-2-ylphenyl)acetate in a 75% yield. In the third step the ethyl (4-pyridin-2-ylphenyl)acetate is saponified to the (4-pyridin-2-ylphenyl)acetic acid with about 95% yield of theory. Consequently, the state of the art synthesis as shown below
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=O)[CH2:29][CH2:30][C:31](OCC)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCCCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of intermediate (S)-ethyl 4-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-4-oxobutanoate (124 mg, 0.25 mmol) in THF (2 mL) was treated with a 1 N THF solution of lithium aluminum hydride (1.0 mL, 1.0 mmol) and stirred for 1 h. After this time the reaction mixture was quenched with ice water (500 μL) followed by a 5% NaOH solution (500 μL) and solid MgSO4. The material was dissolved in EtOAc, filtered and evaporated to afford the title compound as a burgundy colored oil (77 mg. 70%). LC/MS (Method A) 5.22 min, [M+1]+ 439.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.O>C1COCC1>[C:14]([O:13][C:11](=[O:12])[CH2:10][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of p-toluidine (200 mmol) in THF (500 mL) was treated with tert-butyl bromoacetate (220 mmol) and DIPEA (440 mmol) at RT. The reaction mixture was heated to reflux for 16 h and cooled to RT. Water (200 mL) and EE (500 mL) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with water and brine. The solvents were removed in vacuo and the residue (44 g) was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:47]([NH:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[F:39])=[O:48])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C=Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)Nc1ccccc1F
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as the starting materials in 43% yield. LCMS for C25H21ClFN6O (M+H)+: m/z=475.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][N:18]=1)[C:11](OCC)=[O:12].O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[F:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:16]=[CH:17][N:18]=1
Reactant: CCOC(=O)c1ccnc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccnc(F)c1
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a stirred solution of 1.0 M lithium aluminium hydride in anhydrous tetrahydrofuran (7.00 mL, 7.00 mmol) was added at −50° C., under argon, a solution of compound 28 (1.19 g, 7.00 mmol) in anhydrous tetrahydrofuran (10 mL). After 15 min, water (7 mL), a 3.0 N aqueous sodium hydroxide solution (7 mL) and water (7 mL) were added successively to the mixture until no more gas evolution was observed. After return back to room temperature, a brine solution (10 mL) was added. The mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed (Al2O3, CH2Cl2) to give compound 29 (0.45 g, 3.50 mmol) as a beige solid. Yield 51%; Rf (Al2O3, CH2Cl2) 0.32; mp 61-63° C.; IR (KBr) ν 1074, 1273, 1420, 1618, 3100-3400 cm−1; 1H NMR (200 MHz, CDCl3) δ 3.81 (se, 1H), 4.75 (s, 2H), 6.96 (s, 1H), 7.14 (m, 1H), 8.07 (d, 1H, J=5.1 Hz).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[C:19]#[N:20])=[CH:13][CH:12]=2)[S:6]1(=[O:36])=[O:35])([CH3:4])([CH3:3])[CH3:2].[ClH:37].[CH2:38]([OH:40])[CH3:39]>C(Cl)Cl>[ClH:37].[CH2:38]([O:40][C:19](=[NH:20])[CH:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=1)(=[O:24])=[O:23])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[S:6](=[O:35])(=[O:36])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:9](=[O:10])[CH:8]=2)=[CH:16][CH:15]=1)[CH3:39]
Reactant: CCO
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CC(C#N)NS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)S1(=O)=O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)C(Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 1.37-C of Step 3 (87 mg, 0.16 mmol) in methylene chloride (5 mL) and ethanol (0.2 mL) was treated with HCl gas for 1 h. Additional methylene chloride was added during the reaction to replenish the amount which was evaporated during the bubbling of HCl. The reaction mixture was concentrated and used immediately in the next reaction.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[C:9]=1[CH:15]=O)(C)(C)C.[CH3:18][O-].[Na+]>>[N:7]1[C:8]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:15]=[CH:18][CH:6]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Agent: [Na+]
Product: c1cnc2ccncc2c1

Procedure:
Reaction Scheme X illustrates an alternative preparation of the 1,6-naphthyridin-5(6H)-one compounds. In this Scheme, Weinreb amide VIII-2 is reacted with an aryl lithium reagent, generated from aryl bromide X-1, in which R is a protected or masked amino methyl derivative such as 1-(1-azido-1-methylethyl), to give ketone X-2. Condensation of this ketone with tert-butyl(2-chloro-3-formylpyridin-4-yl)carbamate in the presence of sodium methoxide, gives the 1,6-naphthyridine X-3. Deprotection or unmasking of the amine, in this case by palladium catalyzed reduction with hydrogen provides amine X-4. Treatment of X-4 with hydrochloric acid gives 1,6-naphthyridin-5(6H)-one X-5.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1C(O)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:37]3[CH2:36][CH2:35][NH:34][C@H:33]([CH3:32])[CH2:38]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: C[C@@H]1CNCCN1C(=O)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@H](C)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (R)-2-methyl-piperazine-1-carboxylic acid tert, butyl ester and the product purified by SiO2 chromatography (eluting with 93:5:2 dichloromethane:methanol:ammonia).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH:15][CH2:16][C:17](OCC)=[O:18])=[CH:13][CH:12]=[C:11]([O:22][CH3:23])[N:10]=2)[CH2:4][O:3]1.[H-].[Na+].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:24])[O:7][CH2:6][CH:5]([N:8]2[C:17](=[O:18])[CH2:16][NH:15][C:14]3[CH:13]=[CH:12][C:11]([O:22][CH3:23])=[N:10][C:9]2=3)[CH2:4][O:3]1
Reactant: CCOC(=O)CNc1ccc(OC)nc1NC1COC(C)(C)OC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(n1)N(C1COC(C)(C)OC1)C(=O)CN2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Ethyl N-[2-[(2,2-dimethyl-1,3-dioxan-5-yl)amino]-6-(methyloxy)-3-pyridinyl]glycinate (35.42 g, 104.4 mmol) was dissolved in dry THF (500 ml) and the solution was added dropwise over 2 hours to a cooled (0° C.) suspension of sodium hydride (4.173 g of 60% w:w dispersion in oil, 1.00 eq.) in dry THF (500 ml) under argon. During the addition the colour of the suspension changed from orange to green. The mixture was stirred at 0° C. for a further 15 minutes, then allowed to warm to room temperature and stirred at rt for 1 hour. The mixture was cooled to 0° C. and saturated ammonium chloride (15 ml) was added cautiously with vigorous stirring (effervescence observed). After effervescence had ceased, the mixture was allowed to warm to room temperature and stirred for 4 hours then diluted with ethyl acetate (500 ml) and filtered with suction. The solids were washed with ethyl acetate (300 ml) and the combined filtrate plus washings were evaporated under reduced pressure to give a dark brown solid. This was stirred with petroleum ether) (40-60°) (500 ml) plus ethyl acetate (20 ml) for 2 h and filtered with suction to give a lighter brown solid which was washed with petroleum ether) (40-60°) (100 ml) and air-dried to afford the title compound as an amorphous tan solid (25.37 g, 82.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([C:13](=[O:20])[CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]([C:13](=[O:20])[CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: O=C(CN1CCCC1)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)OCCCN2C(=O)CN1CCCC1
Yield: 95.7 %

Procedure:
10% Palladium on Carbon (50% Wet) (0.09 g), 1-(3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone (0.262 g, 0.858 mmol), and hydrazine hydrate (0.25 g, 5.0 mmol) in Ethanol (20 mL) was heated at 60° C. for 5 h. The mixture was cooled, filtered through Celite, washing with 50 mL methanol. The filtrate was conc. and azeotroped 3×30 mL toluene to afford 1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone as a white solid (226 mg, 96%). 1H-NMR (CDCl3): 6.95 (d, 1H, J=8.4 Hz), 6.41 (s, 1H), 6.36 (d, 1H, J=8.4 Hz), 4.82 (d, 1H, J=13.2 Hz), 4.39 (d, 1H, J=12.1 Hz), 3.68 (m, 3H), 3.28 (m, 1H), 2.88 (m, 1H), 2.68 (m, 1H), 2.55 (m, 4H), 2.23 (m, 1H), 1.75 (m, 4H), 1.66 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].Br[C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH3:35])([CH3:34])[C:23]=2[CH:22]=1>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH3:35])([CH3:34])[C:23]=2[CH:22]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccccc3-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene (1.5 g, 2.7 mmol), palladium acetate (616 mg, 2.7 mmol) and sodium tert-butoxide (22.9 g, 238 mmol) are added to a solution of biphenyl-2-ylamine (31.0 g, 183 mmol) and 2-bromo-9,9-dimethyl-9H-fluorene (50.0 g, 183 mmol) in degassed toluene (400 ml), and the mixture is heated under reflux for 20 h. The reaction mixture is cooled to room temperature, diluted with toluene and filtered through Celite. The filtrate is diluted with water and re-extracted with toluene, and the combined organic phases are dried and evaporated in vacuo. The residue is filtered through silica gel (heptane/dichloromethane) and crystallised from isopropanol, giving biphenyl-2-yl-(9,9-dimethyl-9H-fluoren-2-yl)amine in the form of a pale-yellow solid (63.0 g, 95% of theory).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:15][CH2:16]Cl)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[C:21]([CH3:28])[CH:20]=1.[NH2-].[Li+]>CC1C=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:26]#[N:27])[CH2:16][CH2:15][N:4]([S:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:3][CH2:2]2)=[C:21]([CH3:28])[CH:20]=1
Reactant: Cc1cc(F)ccc1CC#N
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccc(F)cc3C)CC2)cc1
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A solution of 29.6 parts of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide and 14.9 parts of 4-fluoro-2-methylbenzeneacetonitrile in 90 parts of methylbenzene is added dropwise to a solution of 5.6 parts of lithium amide in 270 parts of methylbenzene at about 90° C. Upon completion, the whole is heated to reflux and stirred overnight at reflux temperature. The reaction mixture is cooled, poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 27 parts (72.6%) of 4-(4-fluoro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][N:37]([CH2:40][C:41](O)=[O:42])[C:36](=[O:44])[N:35]=2)=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([O:30][CH2:29][C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:32])=[N:35][C:36]1=[O:44])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)cc2)nc1=O
Yield: 86.8 %

Procedure:
The title compound (2.86 g, 87%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid (1.67 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.71 (s, 1H), 8.26 (dd, 1H), 8.16 (dd, 1H), 7.90 (d, 0.6H), 7.82 (d, 0.4H), 7.68˜7.60 (m, 2H), 7.34 (d, 2H), 7.00 (t, 1H), 6.93 (d, 2H), 5.10 (s, 2H), 4.82 (s, 1.2H), 4.61 (s, 0.8H), 4.34 (s, 0.8H), 4.13 (q, 0.8H), 4.05 (s, 1.2H), 4.03 (q, 1.2H), 3.74 (s, 3H), 3.56 (t, 1.2H), 3.40˜3.30 (m, 2H), 3.19 (t, 0.8H), 1.19 (t, 1.2H), 1.12 (t, 1.81H).