Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:24]2[S:25][C:26]([I:30])=[C:27]([CH3:29])[CH:28]=2)=[CH:20][S:21][C:22]=1[NH2:23])=[O:17])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:24]2[S:25][C:26]([I:30])=[C:27]([CH3:29])[CH:28]=2)=[CH:20][S:21][C:22]=1[NH:23][C:4](=[O:5])[CH2:3][C:1]#[N:2])=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c(-c2cc(C)c(I)s2)csc1N
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cc(C)c(I)s2)csc1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.5 %

Procedure:
Cyanoacetic acid (1.2 g, 14.0 mmol) and CH2Cl2 (14 ml) were combined at rt under N2. The solids do not dissolve. PCl5 (2.9 g, 14.0 mmol) was added as a solid portion wise (bubbles vigorously). The suspension was heated at reflux for 30 min and all solids dissolve to give a clear, light yellow solution. The acyl chloride solution was cooled and added directly to 5′-Amino-5-iodo-4-methyl-[2,3′]bithiophenyl-4′-carboxylic acid ethyl ester (2.0 g, 5.1 mmol) in CH2Cl2. The solution was stirred at rt for 2.5 h. The reaction was poured into NaHCO3 (aq, sat.) and washed a second time with NaHCO3 (aq, sat.). The organics were washed with brine and dried (Na2SO4), filtered and concentrated by rotary evaporation to give a light yellow solid which was then triturated with CH3CN and filtered to give 5′-(2-Cyano-acetylamino)-5-iodo-4-methyl-[2,3′]bithiophenyl-4′-carboxylic acid ethyl ester (1.7 g, 3.7 mmol) as a white solid. This material was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[NH2:19][C:20]1[CH:21]=[C:22]([CH:48]=[CH:49][CH:50]=1)[O:23][C:24]1[N:25]=[C:26]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[C:36](Br)[CH:35]=2)[C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O.CN(C)C=O.O1CCCC1>[NH2:19][C:20]1[CH:21]=[C:22]([CH:48]=[CH:49][CH:50]=1)[O:23][C:24]1[N:25]=[C:26]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[C:38]([CH2:3][CH2:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[CH:39]=2)[C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)cnc3C(N)=O)cc2Br)CC1
Reactant: C=CCN1CCOCC1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)cnc3C(N)=O)cc2CCCN2CCOCC2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a mixture of N-allylmorpholine (274 μL) and tetrahydrofuran (5 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 M tetrahydrofuran solution 4.01 mL) under ice-cooling, followed by stirring at 60° C. for 1 hour. After leaving to be cooled, to the reactant were added a mixture of 5-(3-aminophenoxy)-3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (1 g), N,N-dimethylformamide (10 mL), and potassium carbonate (1.39 g), water (1 mL), and a 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride-dichloromethane complex (164 mg), followed by stirring at 60° C. for 40 hours. The reactant was left to be cooled, and then chloroform was added thereto. Then, the insoluble matter was separated by filtration. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1000:10:1-150:10:1) to obtain 5-(3-aminophenoxy)-3-({4-(4-methylpiperazin-1-yl)-3-[3-(morpholin-4-yl) propyl]phenyl}amino)pyrazine-2-carboxamide (67 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Product: O=C1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
5.0 g (19.1 mmol) of 8-(benzyloxymethyl)-1,4-dioxaspiro[4,5]decane was dissolved in 150 ml of 1N aqueous hydrochloric acid solution, and the solution was stirred at room temperature for one hour. The reaction solution was washed twice with 100 ml of chloroform and neutralized with sodium carbonate. The neutralized solution was extracted twice with 100 ml of ethyl acetate and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 4-(benzyloxymethyl)cyclohexanone (3.7 g, 89%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)O)=[CH:5][CH:4]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)c2ccc(-c3ccccc3)s2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2ccc(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of the product of step 2 (0.6 g, 2.0 mmol) in TFA (5 mL) was added triethylsilane (2.4 g, 20.2 mmol) at 0° C., and stirred at room temperature for 4 h. The reaction mixture was poured into ice-water, extracted with EtOAc, washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by a column chromatography on silica gel to yield the title compound (0.55 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)CCC.[Cl-].[Li+]>CN(C)C(=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a degassed solution of 2-bromo-1-fluoro-4-nitrobenzene (6.44 g, 29.3 mmol), 4-tri-n-butylstannylpyridine (14.0 g, 38.0 mmol), lithium chloride (12.4 g, 293 mmol) and copper(I) iodide (0.56 g, 2.93 mmol) in N,N-dimethylacetamide (40 ml) was added tetrakis(triphenylphosphine)palladium(0) (1.69 g, 1.46 mmol) and the reaction heated at 80° C. for 18 h. After cooling to ambient temperature the solvent was evaporated and the residue was diluted with dichloromethane (800 ml) and the mixture stirred vigorously for 30 min then filtered. The organics were washed with water (500 ml) and brine (300 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black oil. The residue was purified by silica gel chromatography eluting with iso-hexane (containing 1% methanol and 1% triethylamine) on a gradient of ethyl acetate (20-50%) to give 4-(2-fluoro-5-nitrophenyl)pyridine as an off-white solid (5.60 g, 88%): δH (360 MHz, CDCl3) 7.38 (1H, t, J 9), 7.50-7.53 (2H, m), 8.30-8.35 (1H, m), 8.41-8.44 (1H, m), 8.76-8.78 (2H, m).
Reaction SMILES: C(C1C=CC2COC3C=CC=CC=3C(=O)C=2C=1)#N.[C:19]1([CH3:28])[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.[Br:29]Br>[Fe]>[Br:29][C:23]1[CH:24]=[C:19]([CH3:28])[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: BrBr
Agent: [Fe]
Agent: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Product: Cc1cc(Br)ccc1C(=O)O

Procedure:
9-Cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin (IIA) may be prepared according to the following general reaction scheme: ##STR5## wherein R2 and R3 are as previously defined, by reacting o-toluic acid with bromine in the presence of iron powder in order to obtain 5-bromo-o-toluic acid. The product obtained from the reaction mixture is predominately the desired 5-bromo isomer although some 3-bromo isomer may be present. If desired, pure 5-bromo isomer can be separated by conventional techniques and employed in pure form as the starting material for subsequent steps. Separation, however, is unnecessary and the product obtained from the reaction mixture usually is employed in the next step without further purification. The 5-bromo acid then is treated with methanol (or any desired lower alkanol) in the presence of a strong acid such as sulfuric acid to form methyl (or lower alkyl) ester which then is treated with N-bromosuccinimide in the presence of benzoyl peroxide under reflux to form methyl (or lower alkyl) α,5-dibromo-o-toluate. The dibromo ester then is reacted with an appropriately substituted R2 and/or R3 phenol in the presence of dimethylformamide and potassium carbonate to obtain the corresponding methyl (or lower alkyl) 5-bromo-α-(R2 and/or R3 substituted phenoxy)-o-toluate. Hydrolysis of the ester with methanol and solium hydroxide yields, on acidification, the free acid when is cyclized in the presence of trifluoroacetic anhydride and boron trifluoride-ethyl ether complex to form the corresponding 9-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin. The cyano group is introduced as previously described by treating the 9-bromo compound with cuprous cyanide in the presence of dimethylformamide in order to obtain the desired R2 and/or R3 substituted 9-cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin of formula IIA.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.CN(P(N(C)C)(N(C)C)=O)C.BrCCC=C.[NH4+].[Cl-]>CCCCCC.C1COCC1>[CH2:9]([C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][CH2:17]1)[CH2:10][CH:11]=[CH2:12]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Agent: C=CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: C=CCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A mixture of diisopropylamine (17.57 mL, 123 mmol) and THF (300 mL) was cooled to −78° C. and 1.6 M solution of n-BuLi (77 mL, 123 mmol) in hexane was added slowly. The mixture was stirred for 15 min, warmed to 0° C. for 20 min and cooled back to −78° C. 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate (25 g, 103 mmol) in THF (25 mL) was added dropwise and the mixture was stirred for 40 min. Then, a mixture of HMPA (17.88 mL, 103 mmol) and 4-bromobut-1-ene (27.7 g, 206 mmol) was added and the mixture was stirred for 1 h before it was warmed to room temp and stir for 16 h. Sat. NH4Cl was then added and the mixture was extracted with ether (2×500 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage (0-20% EtOAc/hexane; 300 g column) to afford 1-tert-butyl 4-methyl 4-(but-3-en-1-yl)piperidine-1,4-dicarboxylate (22 g, 74.0 mmol, 72.0% yield) as light yellow oil. 1H NMR (500 MHz, CDCl3) δ 5.76 (ddt, J=17.0, 10.3, 6.5 Hz, 1H), 5.06-4.92 (m, 2H), 3.94-3.85 (m, 2H), 3.73 (s, 3H), 2.95-2.80 (m, 2H), 2.13 (d, J=13.1 Hz, 2H), 2.02-1.93 (m, 2H), 1.64-1.58 (m, 2H), 1.47 (s, 9H), 1.42-1.32 (m, 2H). LCMS (M+H)=298.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:11][OH:12].C1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+]>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:12][CH2:11][CH2:10][C:13]([F:36])([F:37])[C:14]([F:34])([F:35])[C:15]([F:32])([F:33])[C:16]([F:30])([F:31])[C:17]([F:28])([F:29])[C:18]([F:26])([F:27])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C

Procedure:
10.51 g (53.9 mmol) of bromoacetic acid-tert-butyl ester is added in drops to a mixture of 10 g (21.55 mmol) of 1H,1H,2H,2H-perfluorodecan-1-ol and 0.73 g (2.15 mmol) of tetrabutylammonium hydrogen sulfate in 100 ml of 60% potassium hydroxide solution/50 ml of toluene while being stirred vigorously at 0° C. It is stirred for 1 hour at 0° C. 200 ml of toluene is added, the aqueous phase is separated and extracted twice with 50 ml of toluene each. The combined organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/dichlormethane/acetone=20/10/1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])=[N:2]1.[C:21]([O:28][CH2:29][CH3:30])(=[O:27])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH3:26].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.[NH4+].[Cl-]>[CH2:29]([O:28][C:21](=[O:27])[CH2:22][CH:23]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)[C:12]1=[O:20])[CH2:24][CH2:25][CH3:26])[CH3:30]
Reactant: O=c1[nH]c2ccccc2n1Cc1noc2ccccc12
Reactant: CCC/C=C/C(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Temperature: 60 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 1-1,2-benzisoxazol-3-ylmethyl-1,3-dihydro-benzimidazol-2-one (100 mg, 0.38 mmol) in DMF (5 ml) was added ethyl trans-2-hexenoate (80 mg, 0.57 mmol) followed by benzyltrimethylammonium hydroxide (Triton B, 40 wt % in MeOH, 17.0 ul). The resulting mixture was warmed to 60° C. for 12 h and cooled to ambient temperature. The reaction was diluted with NH4Cl (sat.) and the product was extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 5% EtOAc/dichloromethane). The product-containing fractions were combined and concentrated to give 70 mg (46%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCN1CCOCC1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 58% yield; NMR: 1.96 (m, 2H), 2.13 (s, 3H), 3.29 (m, 4H), 3.5 (m, 4H), 3.59 (m, 4H), 3.69 (m, 4H), 3.92 (s, 3H), 4.18 (m, 2H), 7.08 (m, 1H), 7.13 (s, 1H), 7.22 (s, 1H), 7.28 (m, 1H), 7.58 (m, 1H), 7.75 (m, 1H), 7.81 (s, 1H), 8.27 (m, 2H), 9.39 (s, 1H), 10.29 (s, 1H); M/s: M+H+ 614.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:11]([O:12][CH3:13])[CH2:10][C:9]2[C:8](=[NH:14])[NH:7][C:6](=N)[C:5]=2[CH2:4]1.Cl.[C:17]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:14]=[C:8]1[C:9]2[CH2:10][CH:11]([O:12][CH3:13])[CH:3]([O:2][CH3:1])[CH2:4][C:5]=2[C:6](=[C:29]2[S:28][C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:31][C:30]2=[NH:32])[NH:7]1
Reactant: COC1CC2=C(CC1OC)C(=N)NC2=N
Reactant: N=C1CSC(NCCCc2ccccc2)=N1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COC1CC2=C(CC1OC)C(=C1SC(NCCCc3ccccc3)=NC1=N)NC2=N

Procedure:
When equivalent amounts of 5,6-dimethoxy-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-phenylpropylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-5,6-dimethoxy-4,5,6,7-tetrahydro-3-[2-(3-phenylpropylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[Cl:16][C:17]1[C:18](B(O)O)=[CH:19][C:20]([F:23])=[N:21][CH:22]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.C(OCC)(=O)C.COCCOC>[Cl:16][C:17]1[C:18]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[N:4][CH:3]=2)=[CH:19][C:20]([F:23])=[N:21][CH:22]=1
Reactant: Clc1cncc(NCC2CCOCC2)n1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cc(-c2cncc(NCC3CCOCC3)n2)c(Cl)cn1
Yield: 49.8 %

Procedure:
A mixture of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (1390 mg, 6.10 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (2141 mg, 12.21 mmol), PdCl2(dppf).CH2Cl2 adduct (399 mg, 0.488 mmol), DME (24 ml) and 2M sodium carbonate (9.16 ml, 18.31 mmol) was stirred atl 10-115° C. for 90 min and the reaction progress was followed by LCMS. The reaction mixture was cooled, 30 ml of ethyl acetate and 20 ml of methanol were added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 80 g column eluting with 20-75% ethyl acetate in heptane. The desired fractions were concentrated to constant mass, giving 980 mg of titled compound as free base. LCMS (m/z): 323.0 (MH+), retention time=0.81 min.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:29]=O>>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][CH2:29][C:28]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNCc2ccc(Cl)c(Cl)c2)CC1
Yield: 93.2 %

Procedure:
4-Amino-N-(1-(3-aminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 3,4-dichlorobenzaldehyde (0.99 g) were reacted and treated in the same manner as in Example 121 to give 2.7 g of 4-amino-5-chloro-N-((1-(3-(3,4-dichlorobenzylamino)propyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17][CH:16]2[C:36](O)=[O:37])[CH:12]=[CH:13][CH:14]=1.[NH2:40][C:41]1[CH:45]=[CH:44][N:43]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[N:42]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[OH:49][C:47]([CH3:50])([CH3:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:41]([NH:40][C:36]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:39])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17]2)=[O:37])=[N:42]1
Reactant: CC(C)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1ccc(NC(=O)C2NC(CC(C)(C)CO)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 19.3 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (0.55 g, 0.92 mmol) was reacted with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (0.17 g, 1.1 mmol), EDCI (0.26 g, 1.38 mmol), HOBT (0.19 g, 1.4 mmol) and NEt3 (0.26 mL, 1.8 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.11 g, 20%).
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH: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][CH3:15])[CH3:1]
Reactant: CCCCCCCCCCCCCC(C)O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(C)Br
Temperature: 0 °C

Procedure:
2-Pentadecanol of Example 5 (180 g) and dichloromethane (2500 ml) were added to a 5-litre three-necked flask. The mixture was cooled to 0° C., and carbon tetrabromide (313.6 g) was added and stirred until it dissolved. Triphenylphosphine (351.4 g) was then added dropwise. The resulting mixture was allowed to warm to ambient temperature and left stirring for two days. The reaction mixture was then filtered, and the solvent removed on a rotary evaporator at 56° C. The resulting solid was re-dissolved in heptane and left stirring for two days. It was then filtered through celite under vacuum, and the heptane removed on a rotary evaporator at 78° C. to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:21]1[NH:26][C:25]2=[C:27]([CH2:37][CH3:38])[N:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:29]=[C:24]2[C:23](=[O:39])[NH:22]1)[CH3:2].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[C:21]1[NH:22][C:23](=[O:39])[C:24]2[C:25](=[C:27]([CH2:37][CH3:38])[N:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:29]=2)[N:26]=1)[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C1NC(=O)c2nn(Cc3ccccn3)c(CC)c2N1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 200 °C
Yield: 84.4 %

Procedure:
To a solution of 4-{6-ethoxy-5-[3-ethyl-4,5,6,7-tetrahydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridinylsulfonyl}-1-ethylpiperazine (50 mg, 0.09 mmol, from step (b) above) in toluene (1 mL), was added 10% Pd/C (25 mg, 50% w/w) and trifluoroacetic acid (14 μL). The mixture was heated to 200° C. under nitrogen at 34.5 kPa (5 psi) for 6 hours. The resulting mixture was filtered and concentrated in vacuo to a pale yellow oil. This was dissolved in DCM (5 mL) and washed with NaHCO3 (2 mL), dried over MgSO4 and concentrated to give a brown oil (42 mg, 84%) as product.