Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([Br:11])=[CH:7][N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1)(=O)[CH3:2].[CH3:22]OC(OC)N(C)C.CC(O)=O.[C:34]1([NH:40][NH2:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>Cl>[Br:11][C:8]1[C:9](=[O:10])[C:4]([C:1]2[N:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:41]=[CH:22][CH:2]=2)=[N:5][N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:7]=1
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(Br)c1=O
Reactant: NNc1ccccc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(Br)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 35 %

Procedure:
A mixture of 3-acetyl-5-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (332 mg, 0.92 mmol) and N,N-dimethylformamide dimethyl acetal (3.3 mL) was heated to reflux for 1 h. The mixture was concentrated in vacuo. To the residue were added AcOH (3.3 mL) and phenylhydrazine (0.181 mL, 1.84 mmol). The mixture was heated to reflux for 90 min. To the mixture was added phenylhydrazine (0.091 mL, 0.92 mmol). The mixture was heated to reflux for 90 min. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and by HPLC to yield the title compound (151 mg, 35% yield) as a white solid: mp 145-146° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 7.27 (1H, d, J=1.9 Hz), 7.35-7.52 (6H, m), 7.54-7.64 (2H, m), 7.73 (1H, d, J=8.0 Hz), 7.85 (1H, d, J=1.9 Hz), 9.52 (1H, s). Anal. Calcd for C20H12BrF3N4O: C, 52.08; H, 2.62; N, 12.15. Found: C, 52.07; H, 2.75; N, 12.28.
Reaction SMILES: [OH:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]1[S:10][N:9]=[N:8][CH:7]=1)=[O:4].[CH3:17][N:18]=[C:19]=[O:20]>C(N(CC)CC)C>[CH3:17][NH:18][C:19]([O:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:3]([NH:5][C:6]1[S:10][N:9]=[N:8][CH:7]=1)=[O:4])=[O:20]
Reactant: O=C(Nc1cnns1)N(O)c1ccccc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON(C(=O)Nc1cnns1)c1ccccc1
Reaction time: 0.17 h

Procedure:
4.72 g (0.02 mole) 1-hydroxy-1-phenyl-3-(1,2,3-thiadiazole-5-yl)-urea were suspended in 40 ml tetrahydrafuran and then reacted with 1.19 ml (0.02 mole) methylisocyanate. After addition of 3 drops of triethylamine there is obtained a clear solution and after a further 10 minutes crystals already begin to separate out. The reaction mixture is allowed to stand at room temperature. Thereafter the crystals are separated off and digested with diisopropylether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:28].[Na+:29]>O>[OH2:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O-:17])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1.[Na+:29].[OH2:28].[OH2:13].[Na+:29].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O-:17])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A stirred suspension of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (750 mg.) in water (10 ml.) is treated dropwise at room temperature with 0.4 N-aqueous sodium hydroxide solution (4.50 ml.). The resultant mixture is warmed briefly to 35° C., cooled, and filtered. The filtrate is washed with ether, refiltered, then evaporated in vacuo. The solid residue is dried in vacuo at 100° C. for 12 hours giving sodium 2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate sesquihydrate (0.74 g.) as a solid, which does not melt below 300° C.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].CCN(CC)CC.O>CN(C=O)C>[CH:2]([O:15][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 1-chloro-1,1-diphenylmethane (3.42 g, 16.93 mmol), N-hydroxyphthalimide (2.30 g, 14.11 mmol) and Et3N (3.0 ml) in DMF (50 ml) was stirred at 60° C. under N2 for 8 hours. After the reaction mixture was cooled to room temperature, water (100 ml) was added. The mixture was extracted with Et2O. The combined organic phase was dried over N2SO4. After evaporation of the solvent, the crude product was purified by chromatography (Hexane/Benzene/EtOAc=20/10/3) to give a white solid, 3.95 g (85% yield). 1H NMR (CD3Cl) δ 7.72-7.63 (1H, m), 7.56-7.53 (1H, m), 7.40-7.24 (12H, m), 5.85 (1H, s, Ph2CH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCOCC1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(C)CC3)CC2)nc1N
Yield: 33.1 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (32 mg, 0.066 mmol, Example 272), potassium iodide (50 mg, 0.3 mmol), N-methylpiperazine (500 mg, 5.0 mmol, Aldrich) in dioxane (15 mL) was heated at reflux under nitrogen for 16 hours. The reaction was diluted with methylene chloride (40 mL) and washed (2×) with water. The organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (methanol/methylene chloride) and triturated from ethyl ether and filtered to give (4-amino-2-[1-[3-(4-methyl-piperazin-1-yl)-propane-1-sulfonyl]-piperidin-4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (12 mg, 33% yield). HRMS, observed: 550.2612; Calcd for (M+H)+: 550.2607
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: N#Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, off-white solid, m.p. 147° C. and MS: m/e=330 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-cyano-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:6](CCO)[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH:13]1(N=C=NC2CCCCC2)CCCC[CH2:14]1.[C:28]([OH:47])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].Cl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[NH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([CH2:13][CH2:14][O:46][C:28](=[O:47])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[N:3]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCc1nc(C)[nH]c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of metronidazole (1.9 g) in dry dichloromethane (20 ml) was added successively 4-(N,N-dimethylamino)pyridine (1.22 g), 1,3-dicyclohexylcarbodiimide (2.2 g) and linoleic acid (2.8 g). The mixture was stirred at room temperature overnight. To the reaction was added 2M hydrochloric acid (20 ml) and stirring was continued. After filtration the organic layer was separated, washed with 50% saturated brine and finally with saturated aqueous sodium bicarbonate. The dichloromethane solution was dried (sodium sulfate) and evaporated in vacuo (30° C./20 mm Hg). To the resulting residue was added petrol (bp 30-60° C., 20 ml) and the mixture allowed to stand at room temperature for 2 hours, causing the precipitation of the remaining urea. This was removed by filtration and the filtrate was applied to a dry column giving 2-(2-methyl-5-nitroimidazolyl)ethyl-z,z-octadeca-9,12-dienoate as a pale yellow, non distillable oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[O:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[CH2:20][CH3:21])C>>[C:21]1([CH2:9][CH2:8][CH2:7][C:6](=[O:5])[CH2:1][CH3:2])[CH:20]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Reactant: CCOCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCC(=O)CCCc1ccccc1
Reaction time: 18 h

Procedure:
N-4-bromobenzyl-N-4-phenylbut-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin (0.15 g, approx. 0.75 mmol/g 0.11 mmol) is suspended in diethyl ether (1 mL) and treated with 1 M solution of ethyl magnesium bromide in tetrahydrofuran (0.34 mL, 0.34 mmol). The reaction mixture is agitated for 18 hours, and then quenched by the addition of 2 M HCl (aq) (approx. pH 3 is obtained). The mixture is agitated for 30 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel, washed thoroughly with dichloromethane and concentrated to give of 6-phenylhexan-3-one. GC MS (EI) Area=97.1%, m/z 176.2 (M)+; MS (EI-LRP) m/z 176 (M)+; NMR (300 MHz, CDCl3) δ 1.02 (t, 3H), 1.9 (m, 2H), 2.4 (m, 4H) 2.6 (m, 2H), 7.2-7.3 (m, 5H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([NH:18][C:19]1([CH2:23][C:24](OCC)=O)[CH2:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[OH:30].[NH4+].[Cl-]>C1COCC1>[C:10]([NH:18][C:19]1([C:23](=[O:30])[CH3:24])[CH2:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC1(NC(=O)c2ccccc2)CCC1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1(NC(=O)c2ccccc2)CCC1
Temperature: -78 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
DIBAL (40.0 mL, 1M solution in toluene) was added dropwise at −78° C. to a stirred solution of ethyl [1-(benzoylamino)cyclobutyl]acetate (6.86 g, 26.3 mmol) in THF (130 mL) over the course of 30 minutes. After stirring at −78° C. for 6 hours, MeOH (10 mL) was added dropwise to the mixture at −78° C. over the course of 30 minutes. Saturated aqueous NH4Cl (20 mL) was then added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with Et2O, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (hexane:AcOEt=2:1) of the residue gave the title compound as a colorless solid (1.82 g, 32%). 1H-NMR (400 MHz, CDCl3) δ 1.87-2.07 (2H, m), 2.25-2.34 (2H, m), 2.36-2.45 (2H, m), 3.28 (2H, s), 6.57 (1H, brs), 7.39-7.45 (2H, m), 7.46-7.53 (1H, m), 7.70-7.76 (2H, m), 9.79 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.Br[CH2:32][CH2:33][O:34][CH2:35][CH2:36]Br>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.0 g, 3.30 mmol) obtained in Example 5 was dissolved in tetrahydrofuran (70 ml). At −78° C., a hexane solution (1.57M, 5.3 ml, 8.3 mmol) of n-butyl lithium was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 10 minutes and then stirred for another 30 minutes under ice cooling. At −78° C., 2-bromoethyl ether (0.55 ml, 3.9 mmol) was added dropwise to the reaction mixture. After completion of the dropwise addition, the temperature of the reaction mixture was elevated to room temperature over 14 hours. Water (2.0 ml) was added to the reaction mixture. The residue obtained by concentrating the resulting mixture under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to yield a white solid. The resulting white solid was washed with diisopropyl ether/methylene chloride, whereby the title compound (317 mg, 26%) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][CH3:16])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O.O>[NH3:11].[CH2:23]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)([CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCBr
Reactant: CCCC1(c2cccc(O)c2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(CCC)(c2cccc(O)c2)CC1
Product: N
Temperature: 100 °C
Yield: 154.2 %

Procedure:
To 4-(3-hydroxyphenyl)-4-n-propylpiperidine (Preparation 67, 1.10 g, 5.0 mmol) in N,N-dimethylformamide (25 ml) was added sodium hydrogen carbonate (462 mg, 5.5 mmol) and 1-bromohexane (0.77 ml, 5.5 mmol). The reaction mixture was heated at 100° C. for 3 h 30 min and then allowed to cool to room temperature. The mixture was diluted with water (25 ml) and extracted with dichloromethane (3×25 ml). The combined extracts were washed with water (20 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by (50 g) silica column chromatography eluting with ethyl acetate:hexane:0.880 ammonia (40:60:1) to give the title compound as a pale yellow oil (1.17 g, 77%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH2:12][CH3:13])=[C:10]([CH2:14][CH3:15])[C:9]([CH2:16][CH3:17])=[C:8]2[C:4]=1[C:5](=[NH:19])[NH:6][C:7]2=N)[CH3:2].[ClH:20].[CH:21]([NH:24][C:25]1[S:26][CH2:27][C:28](=[NH:30])[N:29]=1)([CH3:23])[CH3:22].N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:20].[NH:19]=[C:5]1[C:4]2[C:8](=[C:9]([CH2:16][CH3:17])[C:10]([CH2:14][CH3:15])=[C:11]([CH2:12][CH3:13])[C:3]=2[CH2:1][CH3:2])[C:7](=[C:27]2[S:26][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[N:29][C:28]2=[NH:30])[NH:6]1
Reactant: CC(C)NC1=NC(=N)CS1
Reactant: CCc1c(CC)c(CC)c2c(c1CC)C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CCc1c(CC)c(CC)c2c(c1CC)C(=N)NC2=C1SC(NC(C)C)=NC1=N

Procedure:
When equivalent amounts of 4,5,6,7-tetraethyl-1,3-diiminoisoindoline and 2-isopropylamino-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-4,5,6,7-tetraethyl-3-(2-isopropylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)[CH2:2][CH3:3].[CH3:18][CH:19]([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:21][CH:19]([CH3:20])[CH3:18])[C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)[CH2:2][CH3:3]
Reactant: CC(C)N
Reactant: CCCNc1nc(Cl)c2ccn(C(C)C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCNc1nc(NC(C)C)c2ccn(C(C)C)c2n1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To 2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIV, 3.0 g, 12 mmol) in n-butanol (10 mL) was added propan-2-amine (1.05 g, 18 mmol) and potassium carbonate (2.5 g, 18 mmol). The resulting mixture was stirred in an autoclave equipped with a stirrer at 140° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution and dried over anhydrous Na2SO4. After the solvents were removed in vacuo, the residue was purified by flash column chromatography (PE/EtOAc=5/1 to 3/1) to yield 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXV, 1.2 g, 36%) as a yellow solid. LCMS: (ESI) m/z=276 (M+H)+.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 1.5 h

Procedure:
To 450 ml (22.5 mol) of hydrogen fluoride in a stainless steel reaction vessel are added at a temperature of -5 to -1°, 163 g (1.0 mol) of 3-amino-2,5-dichloropyridine. Then there are added while stirring at the same temperature 82.8 g (1.2 mol) of sodium nitrite into the solution The reaction mixture is stirred for 1.5 hours at -5 to -1°, then the temperature is slowly raised to +60° C. After the evolution of gas has ceased, the hydrogen fluoride is distilled off and the residue is taken up in methylen chloride. Ice/water is then added thereto and the cold mixture is neutralized with concentrated ammonium hydroxide solution. The organic phase separated and the water phase is extracted three times with methylene chloride The organic phases are washed with water, dried over magnesium sulfate, filtered through silicagel and evaporated. Thus, 141.5 g (85% of the theory) of 2,5-dichloro-3-fluoropyridine are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].C([Li])CCC.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([F:29])[CH:22]=1>C(OCC)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[OH:26])=[C:23]([F:29])[CH:22]=1
Reactant: CCOC(OCC)c1ccccc1Br
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(OCC)c1ccccc1C(O)c1ccc(Br)cc1F
Reaction time: 0.75 h

Procedure:
To a mechanically stirred solution of 1-bromo-2-(diethoxymethyl)benzene (266 g) in dry diethyl ether (1.5 ) cooled to −70° C. under nitrogen was added a 2.5M solution of n-butyl lithium in hexanes (414 mL) dropwise over 30 min. The reaction mixture was stirred at a temperature less than −60° C. for 45 min then a solution of 4-bromo-2-fluorobenzaldehyde in dry diethyl ether (1.5 ) was added dropwise over 1 h maintaining the low temperature. The cooling bath was removed allowing the reaction to warm to +10° C. over 3 h. The reaction was quenched by the addition of water (500 mL). Organic layer was separated and the aqueous layer washed with ethyl acetate (2×500 mL). Combined organic layers were washed with brine then dried over anhydrous sodium sulfate and evaporated to yield the title product (371.1 g) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1NS(=O)(=O)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c1C(=O)NS2(=O)=O

Procedure:
3.0 gm (13 mmols) of 4-nitro-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide were dissolved in 100 ml of ethanol. The solution was hydrogenated with hydrogen, using a palladium/animal charcoal catalyst. After filtration, evaporation and recrystallization from ethanol 2.3 gm (89.5% of theory) of the amino compound were obtained.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3.C[Si](C)(C)CCOC[N:30]1[C:34](B(O)O)=[CH:33][CH:32]=[N:31]1.[C:40](=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.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>[CH3:40][C:34]1[CH:33]=[C:32]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]3=[N:4][CH:3]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=4)[NH:31][N:30]=1
Reactant: O=C([O-])[O-]
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(Br)cnc12
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(1-bromo-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (1 eq), 1-[2-(trimethylsilyl)ethoxymethyl]-pyrazole-5-boronic acid (2 eq) and sodium carbonate (3 eq) in N,N-dimethylformamide degassed under argon for 10 minutes was added tetrakis(triphenylphosphine)palladium (0.3 eq). The mixture was allowed to stir for 3 hours at 100° C. The crude mixture is cooled to room temperature, diluted with ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic phase was separated and the aqueous phase was extracted again twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, mixture of dichloromethane/methanol) to afford the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:9]=[N:8][C:7]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[CH:6]2.O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:23][C:17]1[CH:16]=[C:15]([C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=3[O:13][CH3:14])[CH:20]=[C:19]([CH3:21])[C:18]=1[O:22][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(OC)c2cnc(-c3cc(C)c(O)c(C)c3)cc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)c2cnc(-c3cc(C)c(OCCN4CCOCC4)c(C)c3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (0.309 g, 1.0 mol) in anhydrous THF (20 mL), triphenyl phosphene (0.52 g, 2.0 mmol), 4-(2-hydroxyethyl)morpholine (0.262 g, 2.0 mmol) and N,N-diisopropylethylamine (0.387 g, 3.0 mmol) were added. To this stirred solution was added diethylazodicarboxylate (0.348 g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen, then diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography to give 3-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-6,8-dimethoxyisoquinoline (0.54 g) as a white solid.