Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N+:33]([O-:35])=[O:34])=[CH:19][CH:18]=1>C(#N)C>[CH2:7]([N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N+:33]([O-:35])=[O:34])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(CCCC)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)n1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Potassium carbonate (54 mg, 2 eq) and a solution of dibutylamine (30 mg, 1.2 eq) in acetonitrile (2 ml) are added successively to a solution of 6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine (59 mg, 1 eq) in acetonitrile (3 ml). The mixture is heated to reflux for 15 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (90 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue obtained, by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1 to 100% ethyl acetate), produces the expected compound (73 mg; 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]2=[O:22])=[C:4]([O:23][CH3:24])[CH:3]=1.C(Cl)Cl.[NH2:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:28][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]2=[O:22])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)ccc1-n1c(=O)cnc2cc(S(=O)(=O)Cl)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)ccc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A RBF was charged with 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride (0.800 g, 1.862 mmol), DCM (3.12 ml), and 3-aminoisoxazole (0.206 ml, 2.79 mmol) to give a thick suspension. Pyridine (6.21 ml) was added relatively quickly, leading to thinner suspension. After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-50% 3:1 EtOAc/EtOH in heptane with 10% DCM) to give 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (0.751 g, 1.573 mmol, 85% yield) as a white foam. m/z (ESI) 478.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][CH:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17]Br>O1CCOCC1>[C:21]1([CH2:20][O:19][CH:16]2[CH2:17][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCC(CBr)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a stirred suspension of oil-free sodium hydride (10.7 g, 0.446 mol) in 270 ml of dry dioxane under nitrogen at room temperature was added over twenty minutes 69.1 g (0.432 mol) of diethyl malonate. After the addition, 1-chloro-2-benzyloxy-3-bromopropane (115 g, 0.437 mol) was added over 20 minutes, and the reaction was refluxed for 44 hours. The reaction was cooled to room temperature, and then a slurry of 10.7 g (0.446 mol) of oil-free sodium hydride in 100 ml of dioxane was cautiously added in portions. The mixture was refluxed for 120 hours and cooled to room temperature. The inorganics were removed by filtration, and the filtrate was concentrated in vacuo to an oil, which was partitioned between ether and water. The ether layer was dried (Na2SO4) and concentrated to an oil, which was distilled to give 58.8 g of desired product having a b.p. 142°-146°/0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(N(CC)CC)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[N:13]2[CH2:18][CH2:17][N:16]([C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2oc3ccccc3c2N2CCNCC2)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)N1CCN(c2c(-c3ccc(Cl)cc3)oc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
To the solution of 56 g of 1-(2-p-chlorophenyl-3-benzofuryl)piperazine in 25.2 g of triethylamine and 500 ml of methylene chloride, 31.7 g of pelargonic acid chloride in 300 ml of methylene chloride are added while stirring at 0° for 1/2 hour and stirring is continued for 15 hours. The mixture is washed successively with 1 N-hydrochloric acid, 2 N-aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated to yield the 1-(2-p-chlorophenyl-3-benzofuryl)-4-pelargonylpiperazine as an oil showing in the 1R-spectrum characteristic bands at 1640 and 812 cm-1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[S:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[N:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35]([C:33]2[N:32]=[N:31][S:30][CH:34]=2)=[O:36])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1csnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3csnn3)c2F)c1
Reaction time: 8 h
Yield: 47.3 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 1,2,3-thiadiazole-4-carboxylic acid (10.46 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.016 g, 46%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 9.55 (s, 1H), 8.94 (br. s., 1H), 7.63 (t, 1H), 7.53 (t, 1H), 7.41-7.46 (m, 1H), 7.37-7.41 (m, 2 H), 4.79 (d, 2H). LCMS m/z 422.8 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:43]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:43])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(OCCCSC)cc3)oc2C)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(OCCCS(C)=O)cc3)oc2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(2-methyl-5-{4-[3-(methylsulfanyl)propoxy]phenyl}furan-3-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (296 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (277 mg) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% methanol/ethyl acetate to 20% methanol/ethyl acetate) to give the title compound (278 mg, 91%) as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([O:29][C:30]([N:32]1[CH:36]=[C:35]([C:37]([OH:39])=O)[C:34]([CH3:40])=[N:33]1)=[O:31])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:68])[C:62]4[CH:63]=[N:64][NH:65][C:66]=4[CH:67]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C.CS(C)=O>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:67]=[C:66]4[C:62]([CH:63]=[N:64][NH:65]4)=[C:61]([NH:68][C:37]([C:35]4[C:34]([CH3:40])=[N:33][N:32]([C:30]([O:29][C:26]([CH3:25])([CH3:27])[CH3:28])=[O:31])[CH:36]=4)=[O:39])[CH:60]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C(=O)OC(C)(C)C)cc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
To a solution of HATU (0.162 g) in anhydrous DMF (4 ml) was added 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1H-pyrazole-4-carboxylic acid (0.097 g) and DIPEA (0.149 ml) and the mixture was left to stand for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (0.053 gl) dissolved in anhydrous DMF (3 ml) was added and the solution was left to stand at RT for 18 h. The DMF was blown down to dryness under a stream of nitrogen and the residue was dissolved in DMSO:methanol (1 ml, 1:1) and purified by MDAP (method K). The solvent was removed in vacuo to give title compound, 6 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (400 mg, 0.99 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) (513 mg, 1.98 mmol) in dimethylformamide (6 mL) were added N,N-diisopropylethylamine (0.5 mL, 2.97 mmol) and HATU (564 mg, 1.48 mmol). Stirring was continued at room temperature for 1 h. Water (75 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (308) (540 mg, 84.53%) as a colorless sticky solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C1C2C(=CC=CC=2)C=C(N)N=1>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[C:7]([NH:12][C:13]([CH:15]2[CH2:16][CH2:17]2)=[O:14])[N:8]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Nc1cc2ccccc2cn1
Product: O=C(Nc1cc2ccccc2cn1)C1CC1

Procedure:
The title compound was synthesized following the same method as described for the synthesis of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide, using commercially available isoquinolin-3-amine instead of 7-bromo-isoquinolin-3-amine. LCMS (ESI): RT (Min)=3.537, M+H=213.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.14 (s, 1H), 8.45 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 2.06 (d, J=4.4 Hz, 1H), 0.89-0.77 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][C:44]1[CH:45]=[C:46]([C@@H:51]([O:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:60]=[CH:59]3)[C@@H:52]([NH2:54])[CH3:53])[CH:47]=[CH:48][C:49]=1[CH3:50]>CN1C(=O)CCC1>[CH3:43][C:44]1[CH:45]=[C:46]([C@@H:51]([O:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[N:60]=[CH:59]3)[C@@H:52]([NH:54][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:9])[CH3:53])[CH:47]=[CH:48][C:49]=1[CH3:50]
Reactant: Cc1cnc(C(=O)O)s1
Reactant: Cc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cnc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2ccc(C)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-methyl-1,3-thiazole-2-carboxylic acid (29 mg, 0.2 mmol) was dissolved in NMP (1 mL) together with HATU (76 mg, 0.2 mmol) and DIEA (133 uL, 0.8 mmol). The mixture was stirred in r.t. for 5 min before (1R,2S)-1-(3,4-dimethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (58 mg, 0.15 mmol, prepared analogously to Example 6a with corresponding starting material) was added. The reaction mixture was stirred in r.t. overnight before it was evaporated under reduced pressure and purified by semi-prep. HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]([CH3:33])[CH3:32])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)Cl
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)C
Yield: 49 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(isopropylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 49% yield; NMR spectrum (DMSO-d6) 1.19 (d, 6H), 2.07 (s, 3H), 3.77 (t, 2H), 4.06-4.14 (m, 1H), 4.34 (t, 2H), 5.31 (s, 2H), 7.21 (d, 1H), 7.27 (d, 1H), 7.32-7.39 (m, 2H), 7.57-7.63 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.91 (m, 1H), 8.01 (d, 1H), 8.46 (s, 1H), 8.60 (d, 1H), 10.00 (s, 1H); Mass spectrum MH+ 506.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Br
Temperature: 100 °C
Reaction time: 5 h

Procedure:
The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of 2,5-dibromobenzoic acid (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70° C. The reaction mixture was vigorously stirred, heated to 100° C. and then kept at 100° C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229° C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH2:16])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3N)[nH]c2cc1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)[nH]c2cc1CC
Reaction time: 48 h
Yield: 83.9 %

Procedure:
A solution of 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine [0.3 g, Reference Example 49(a)] and triethylamine (0.8 mL, excess) in tetrahydrofuran (20 mL) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). This mixture was stirred for 48 hours then diluted with aqueous sodium bicarbonate solution (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was dissolved in tetrahydrofuran (50 mL). This solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 mL) and the mixture was stirred for 2 hours, then poured into water (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1, v/v) to give cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide (0.3 g) as an off-white solid. LC-MS (Method E): RT 2.99 minutes, 424 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-])=O)=[C:4]([Cl:15])[N:3]=1>C(O)(=O)C.[Fe]>[NH2:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([Cl:1])=[N:3][C:4]=1[Cl:15]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1nc(Cl)nc(Cl)c1N
Temperature: 60 °C
Yield: 47.3 %

Procedure:
A mixture of methyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (5 gm, 20 mmol) and powdered iron (5 gm) in acetic acid (40 mL) was heated at 60° C. There was a vigorous exotherm within 5 minutes and the reaction was allowed to cool to room temperature. The acetic acid was removed and the residue was suspended in a mixture of water and diethyl ether. This was filtered and the solid was washed with diethyl ether. The organic phase was separated, washed with saturated aqueous NaHCO3 solution (twice) and brine, dried over sodium sulfate, and the solvent removed to leave methyl 5-amino-2,6-dichloropyrimidine-4-carboxylate (2.1 gm) as a yellow brown solid. MS (ESI) m/z 222.0 and 224.0 (M+H). 1H NMR (CDCl3) δ ppm 6.20 (2H, br. s.), 3.99 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([NH:47][CH2:46][C:43]2[CH:42]=[CH:41][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:45][CH:44]=2)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10]
Reactant: NCc1ccc(C2=NCCN2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc(C(=O)NCc2ccc(C3=NCCN3)cc2)co1)S(=O)(=O)c1c(Cl)cccc1Cl

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (51 mg, 0.14 mmol) was dissolved in DCE (0.5 mL) and CDI (34 mg, 0.21 mmol) was added. The mixture was stirred until acid activation was complete. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methanamine.HCl (180 mg, 0.42 mmol) and DIPEA (0.22 mL, 1.26 mmol) were sonicated in DMF (3 mL) for 15 min, 0.25 mL of activated acid solution was added to 0.5 mL of amine solution and the reaction was diluted with DMF (1.5 mL) and stirred at ambient temperature for 18 h. The reaction was concentrated, dissolved in DCM and washed with water (3×1.5 mL) and saturated brine (1 mL)). The organic layer was dried over MgSO4, shaken with Ambersep and PL-MIA resins, and solvents were removed in vacuo. A portion of the crude product was purified using prep method C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:6]=[N:5]1.FC(F)(F)C(O)=O.N>>[OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:6]=[N:5]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCO)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cnn(CCO)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 88.8 %

Procedure:
(S)-2-(1-((5-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (33 mg, 0.05 mmol) was treated with trifluoroacetic acid (1.5 mL, 19.47 mmol) and a solution of ammonia (7N in methanol, 2 mL, 14 mmol) according to the method described in Example 27 to give 22 mg (84% yield) of the title compound. Purity 100%.