Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:23][C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:35]([NH2:37])=[O:36]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:23][C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[N:26][C:25]=2[C:35]([NH2:37])=[O:36])=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: NC(=O)c1nc(-c2ccncc2)sc1N
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2sc(-c3ccncc3)nc2C(N)=O)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
4-Methylbenzoic acid (0.054 g, 0.0004 mol) and carbonyl di-imidazole (CDI) (0.097 g 0.0006 mol), are dissolved in dry DMF (2 ml) and stirred at 90° C. for 1 hr, then 5-amino-2-pyridin-4-yl-thiazole-4-carboxylic acid amide (0.05 g, 0.0002 mol) is added and the mixture is stirred overnight at 90° C. After the completion of the reaction is evidenced from TLC, solvent is evaporated and the crude product is purified by silica gel column chromatography to afford 17.6 mg 5-(4-methyl-benzoylamino)-2-pyridin-4-yl-thiazole-4-carboxylic acid amide (“A55”) (17.6 mg, 32.46% yield);
Reaction SMILES: [FH:1].Cl[C:3]1([F:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]1([F:14])[F:13]>>[F:1][C:3]1([F:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]1([F:14])[F:13]
Reactant: F
Reactant: FC1(F)Oc2ccccc2OC1(F)Cl
Product: FC1(F)Oc2ccccc2OC1(F)F
Yield: 98 %

Procedure:
Subsequently, 140 ml/h of hydrogen fluoride (measured as liquid) and 110 g/h of 2-chloro-2,3,3-trifluorobenzodioxane were passed over the catalyst at 300° C. In the course of 6 hours, 600 g of 2,2,3,3-tetrafluorobenzodioxane were obtained. This corresponds to a yield of 98%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])O.[Na+].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1COCC1>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: NCCn1ccnn1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(NCCn1ccnn1)c1ccc(O)cc1
Reaction time: 4 h
Yield: 72 %

Procedure:
To a mixture of 9.31 g (83.1 mmol) 2-[1,2,3]triazol-1-yl-ethylamine and 13.96 g (166 mmol) sodium hydrogencarbonate in 320 ml THF was added dropwise a solution of 16.0 g (83.1 mmol) 4-hydroxy-benzenesulfonylchloride in 160 ml THF at room temperature. Stirring was continued at 80° C. for 4 hours, then the solvent was evaporated and the residue triturated with 100 ml water to leave 16.05 g (72%) title compound as white solid melting at 220–223° C. (dec).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C(=O)C.C(O)C.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Cc1cc(Br)cc2nnc(Nc3ccccc3)nc12
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1-c1cc(C)c2nc(Nc3ccccc3)nnc2c1
Yield: 46.4 %

Procedure:
To a solution of (7-Bromo-5-methyl-benzo[1,2,4]triazin-3-yl)-phenyl-amine (60 mg, 0.19 mmol) dissolved in 3 ml N,N-Dimethylacetamide in a 20 ml vial, 2,6-dimethyl-phenylboronic acid (114 mg, 0.76 mmol) dissolved in 2 ml ethanol and potassium carbonate (31 mg, 0.3 mmol) dissolved in 1 ml water were added. Triphenylphosphine (4.5 mg, 0.0171 mmol) and tris(dibenzylideneacetone) dipalladium (0) (4.5 mg, 4.9 umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 30 mg [7-(2,6-Dimethyl-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 46%; ESI-MS: [M+H]+, 341; 1H NMR (DMSO-d6): δ 2.05 (s, 6 H), 2.67(s, 3H), 7.07(t, J=7.33 Hz, 1 H), 7.17–7.24 (m, 3 H), 7.41 (t, J=7.56 Hz, 2 H), 7.62 (d, J=1.49 Hz, 1 H), 7.93 (d, J=1.49 Hz, 1 H), 8.05 (d, J=7.72 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])CCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C.Cl>C1COCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:19]([OH:20])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: COCOCc1cc(F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB1OCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:32])=[C:20]([NH:22][C:23]([C:25]5[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=5)=[O:24])[CH:21]=4)=[N:11][N:10]3[CH:33]=2)=[O:5])CC1.CO.[ClH:36].[CH3:37][N:38]1[CH2:43][CH2:42][N:41](CC(O)=O)[CH2:40][CH2:39]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[ClH:36].[ClH:36].[F:32][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([CH:33]=[C:7]([NH:6][C:4](=[O:5])[CH2:1][N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[N:8]=3)[N:11]=2)=[CH:21][C:20]=1[NH:22][C:23]([C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1)=[O:24]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CN5CCN(C)CC5)cn4n3)ccc2F)n(C)n1
Temperature: 50 °C
Reaction time: 44 h
Yield: 6 %

Procedure:
To N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.05 mg, 2.33 mmol) was added 10% hydrogen chloride methanol solution (120 mL), and the mixture was stirred at 50° C. for 44 hr. The solvent was evaporated under reduced pressure. To a half of the residue were added (4-methylpiperazin-1-yl)acetic acid (205 mg, 1.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 mmol), 1-hydroxybenzotriazole (167 mg, 1.24 mmol), N-ethyldiisopropylamine (0.60 mL, 3.51 mmol) and N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 11 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→70/30) and the objective fraction was concentrated under reduced pressure. The residue was dissolved in methanol and treated with a 4N hydrogen chloride ethyl acetate solution to give the title compound (43 mg, 6%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[C:18]([C:14]1[CH:13]=[C:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:17]=[CH:16][CH:15]=1)#[CH:19]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C#Cc1cccc(N)c1
Solvent: c1ccncc1
Product: C#Cc1cccc(Nc2ncnc3[nH]cnc23)c1
Temperature: 85 °C
Yield: 3.3 %

Procedure:
To 6-chloropurine (1.0 g, 6.5 mmol) in dry pyridine (10 ml) was added m-aminophenyl acetylene (0.91 g, 7.8 mmol). The mixture was heated in an 85° C. oil bath for 23 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The oily residue was partitioned between CH2Cl2 and H2O then filtered to afford the title compound as a light orange solid (50 mg, 3.3%). LC-MS: 236 (MH+); anal. RP18-HPLC RT: 3.25 min.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.C(NCC)C>[NH2:1][C@H:2]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: ClCCl
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Fmoc-Asn(Trt)-OBn (3.5 g, 5.1 mmol) in DCM (14.0 mL), diethylamine (14.0 mL) was added and stirred for 1 h at rt. The resulting solution was concentrated in vacuo and the thick-residue was purified by neutral alumina column chromatography (eluent: 0-50% EtOAc in Hexane then 0-5% MeOH in CHCl3) to yield NH2-Asn(Trt)-OBn D (yield: 1.75 g, 73.0%; Mass: Cal. 464.21, Obs—465.3 (M+1), 487.2 (M+Na]).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 160–162° C.; 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 1 H), 6.67 (d, J=2.2 Hz, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.37 (t, J=7.7 Hz, 2 H), 4.29–4.04 (m, 1 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.07 (s, 3 H), 1.95–1.75 (m, 2 H), 1.08–1.00 (m, 1 H), 0.95 (t, J=7.5 Hz, 3 H), 0.82–0.75 (m, 1 H), 0.57–0.47 (m, 2 H), 0.36–0.29 (m, 1 H); HRMS (ESI) calcd for C20H25N3O2Cl (M+H)+: 374.1635; found m/z 374.1617.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:7]([OH:9])=[O:8].[CH2:16](O)[CH3:17]>>[NH2:5][C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCO
Reactant: CC(N)(C(=O)O)c1cccs1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(N)c1cccs1
Yield: 86 %

Procedure:
Thionyl chloride (1 mL, 14.6 mmol) was added dropwise to 2-amino-2-(thiophen-2-yl)propanoic acid (0.500 g, 2.92 mmol) suspended in anhydrous ethanol (10 mL) at 0° then the reaction was heated at reflux for 22 hours. The reaction was concentrated by rotary evaporation, diluted with water (5 mL), adjusted pH to 9 with 6N aqueous sodium hydroxide, and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.498 g, 2.499 mmol, 86%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.17 (t, J=7.17 Hz, 3 H) 1.60 (s, 3 H) 2.53 (s, 2 H) 4.11 (q, J=7.23 Hz, 2 H) 6.91-6.98 (m, 1 H) 7.00 (dd, J=3.68, 1.10 Hz, 1 H) 7.37 (dd, J=5.15, 1.10 Hz, 1 H). MS (DCI) m/z 200 (M+H)+, 217 (M+NH4)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH3:10])=[CH:4][N+:3]=1[O-].P(Cl)(Cl)Cl>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: Cc1c[n+]([O-])c(N)c(C#N)n1
Solvent: ClP(Cl)Cl
Product: Cc1cnc(N)c(C#N)n1

Procedure:
The intermediate 2-amino-5-methylpyrazine is prepared stepwise, starting with 2-oxopropanal 1-oxime. This oxime is allowed to react with aminomalononitrile tosylate [prepared by the method of Ferris et al., J. Am. Chem. Soc. 88, 3829 (1966)], to yield 2-amino-3-cyano-5-methylpyrazine 1-oxide. The pyrazine 1-oxide prepared in this manner is allowed to react with phosphorous trichloride to yield 2-amino-3-cyano-5-methylpyrazine. This 2-amino-3-cyano-5-methylpyrazine is hydrolyzed with aqueous sodium hydroxide to yield 2-amino-3-carboxy-5-methylpyrazine, which, when heated in tetrahydronaphthalene, is decarboxylated to yield the desired 2-amino-5-methylpyrazine.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])=[N-].[C:10]([OH:13])(=[O:12])[CH3:11]>>[C:10]([O:13][CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])(=[O:12])[CH3:11]
Reactant: C=CCCC(=O)C=[N+]=[N-]
Reactant: CC(=O)O
Product: C=CCCC(=O)COC(C)=O
Yield: 90 %

Procedure:
Into 35 ml of glacial acetic acid at 60°-70° C. is dropped slowly 12.4 g. (0.1 mole) of 1-diazo-5-hexen-2-one. After the nitrogen evolution stops, the reaction mixture is heated to reflux for one hour. The resulting mixture is extracted with 3×50 ml of methylene chloride. The organic layer is dried over anhydrous magnesium sulfate. Concentration of the filtrate gives 1-acetoxy-5-hexen-2-one as a brown oil in 90% yield, based on the starting 4-pentenoyl chloride. ##STR40##
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].F[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCOCC1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCCOc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspention of NaH (100 mmol, 55-65% in oil) in dry dioxane (140 mL) was added 3-dimethylamino-1-propanol (11.90 mL, 100 mmol). The mixture was stirred 1 h at room temperature. A solution of 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (9.53 g, 33.35 mmol, preparation described in example 66) in dry dioxane (35 mL) was added. The resulting mixture was heated 24 h at 100° C. Solvents were evaporated. NH4Cl saturated solution in water (75 mL) was added and the desired product was extracted with three portions of ethyl acetate (3×100 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. N-(4-chlorophenyl)-4-[3-(dimethylamino)propoxy]benzenesulfonamide was obtained as a colorless oil, in 96% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[Cl:11])[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2Cl)c1

Procedure:
4-Bromo-2-chlorobenzoic acid (132 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:30]([CH2:31][CH3:32])[CH2:29][CH2:28][O:27][CH3:26])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNCCOC
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CCN(CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and N-(2-Methoxyethyl)ethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-(2-methoxy-ethyl)-amine, MS: 403 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH3:13]C(=O)CCCCCCCCCCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:13]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: CCCCCCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 174.3 %

Procedure:
A stirred mixture of 26.05 g of 1,8-diaminonaphthalene, 32.66 g of 2-tridecanone, 55 mg of p-toluenesulfonic acid monohydrate, and 250 mL of toluene was heated to reflux under a nitrogen atmosphere using a Dean-Stark trap to remove the water evolved from the reaction for 5 hr. The mixture was then washed with saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, filtered, and the solvent removed under reduced pressure. The product was distilled to yield 48.86 g of dihydroperimidine intermediate, bp 192°-213° C. at 0.3 to 0.4 torr.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:61][S:62][S:63][C:64]([CH3:67])([CH3:66])[CH3:65])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])=O)(C)(C)C>>[NH2:15][C@@H:16]([CH2:61][S:62][S:63][C:64]([CH3:67])([CH3:66])[CH3:65])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:59])([OH:60])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSC[C@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 121.1 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy) (hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-A) (40 mg, 0.045 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-3-(tert-butyldisulfanyl)propanoate (Compound 2n-A) (45.1 mg, 100%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.Br[C:36]1[CH:45]=[C:44]2[C:39]([C:40]3[N:49]4[CH2:50][CH2:51][CH2:52][N:53]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:54][C:48]4=[N:47][C:41]=3[C:42]([NH2:46])=[N:43]2)=[CH:38][CH:37]=1>C(O)CC.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:58][S:55]([N:53]1[CH2:52][CH2:51][CH2:50][N:49]2[C:40]3[C:39]4[C:44](=[CH:45][C:36]([C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)=[CH:37][CH:38]=4)[N:43]=[C:42]([NH2:46])[C:41]=3[N:47]=[C:48]2[CH2:54]1)(=[O:57])=[O:56]
Reactant: OB(O)c1cccnc1
Reactant: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4cc(Br)ccc4c32)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4cc(-c5cccnc5)ccc4c32)C1
Temperature: 80 °C
Yield: 17.1 %

Procedure:
Sodium carbonate (0.140 g, 1.32 mmol), triphenylphosphine (74.7 mg, 0.33 mmol), 3-pyridine boronic acid (0.149 g, 1.21 mmol), and palladium (II) acetate (25 mg, 0.11 mmol) were sequentially added to a solution of 3-bromo-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine (0.450 g, 1.1 mmol) in n-propanol (15 mL), methanol (10 mL), and water (5 mL). The reaction was heated at 80° C. overnight and then concentrated under reduced pressure. The residue was mixed with dichloromethane, and the resulting solid was isolated by filtration. The solid was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a gradient from 0% to 25%. The resulting solid was mixed with material from another run and purified again by column chromatography on silica gel under the same conditions to provide 76.8 mg of 9-(methylsulfonyl)-3-pyridin-3-yl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine, as a beige solid, mp 302° C.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:33])=[CH:13][C:12]=3[F:34])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35]I>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:28][CH:29]([O:32][CH3:35])[CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:33])=[CH:13][C:12]=3[F:34])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(O)COc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Reactant: CI
Product: CCC(COc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1)OC

Procedure:
According to Method AA, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-(2-hydroxy-butoxy)-2H-isoquinolin-1-one was reacted with methyl iodide. In this way the product was obtained with molecular weight 479.60 (C28H34FN3O3); MS (ESI): 480 (M+H+).