Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([NH:21]C(=O)C)([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)([NH2:21])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(N)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Yield: 55.7 %

Procedure:
A stirred solution of N-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide (Example 69) (0.04 g, 0.12 mmol) in concentrated HCl (0.07 mL, 3.03 mmol) was heated at 100° C. for 24 hrs in a sealed glass tube. The reaction mixture was then cooled to room temperature and neutralized with 10% NaOH solution (2 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were concentrated under vacuum. The crude product residue obtained was purified by preparative TLC using eluting solvent as MeOH:CH2Cl2 (3:7) to afford 20 mg (38%) of 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanamine as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, 2H, J=5.6 Hz), 7.91-7.88 (m, 2H), 7.70 (s, 1H), 7.51 (d, 2H, J=6.4 Hz), 7.28 (t, 2H, J=8.8 Hz), 2.81 (s, 2H); 1.85 (s, 3H); LC-MS m/z calculated for [M+H]+ 300.09, found 300.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=[O:16].[CH3:19][OH:20]>>[CH:6]1[C:7]2[C:19](=[O:20])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:1](=[O:16])[C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1Cc1ccccc1
Reactant: CO
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
A process for the manufacture of anthraquinones in which o-benzyl-toluene is first oxidized with 25 to 50 weight-% nitric acid at atmospheric pressure and moderate temperatures, and then further oxidized with a more dilute nitric acid at elevated temperatures and pressures to yield crude o-benzoyl-benzoic acid. The crude product is then esterified with methanol, the methyl ester distilled and, when necessary, recrystallized, and heated with concentrated sulfuric acid to yield anthraquinone in high yield and of a high degree of purity.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].N1C(C)=CC(C)=CC=1C>CCCCCC.CC(C)=O>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: CC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCCC
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
Methyl pheophorbide-a (100 mg, 0.17 mmol) was added to commercially available 2,4,6-collidine (25 mL, Aldrich) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 10 min, the reaction was shown to have reached 100% completion by HPLC peak area. The solution was cooled to room temperature and solvent removed under reduced pressure. Hexane (10 mL) was added to the flask and the precipitated residue collected by filtration and rinsed with hexane to give methyl pyropheophorbide-a (71 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=O)=[N:10][CH:11]=1.CCO.[OH2:21].Cl.[NH2:23]O.[OH-].[Na+]>CC(O)=O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[N:23][OH:21])=[N:10][CH:11]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2Cl)cn1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: ON=Cc1ccc(OCc2ccccc2Cl)cn1
Temperature: 0 °C
Yield: 69 %

Procedure:
5-(2-Chloro-benzyloxy)-pyridine-2-carbaldehyde (which may be prepared as described in Preparation of Intermediate 7; 2.06 g, 8.3 mmol) was suspended in 9:1 EtOH/H2O (20 mL) and hydroxylamine hydrochloride (1.45 g, 20.9 mmol) was added. A solution of 3.25 M NaOH in 9:1 EtOH/H2O (6.5 mL, 21.1 mmol) was added slowly dropwise. The mixture was heated under reflux for 2.5 h and then cooled to 0° C. The pH was adjusted to 4 by the addition of glacial AcOH. The precipitate was filtered off to give 5-(2-chloro-benzyloxy)-pyridine-2-carbaldehyde oxime (1.5 g, 69%) as an off-white solid.
Reaction SMILES: Cl.C([O:4][C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:20]2[S:21][CH:22]=[N:23][C:19]=2[CH2:18][CH2:17][NH:16]1)C.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[CH2:36][N:37]=[C:38]=[S:39].[OH-].[Na+]>CC#N.C(O)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:4])=[O:24])=[C:9]([CH:15]2[C:20]3[S:21][CH:22]=[N:23][C:19]=3[CH2:18][CH2:17][N:16]2[C:38](=[S:39])[NH:37][CH2:36][C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=2[O:33][CH3:32])[CH:10]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ncsc21
Reactant: COc1ccccc1CN=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=S)N1CCc2ncsc2C1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.00 eq.) and NEt3 (54 μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL), 2-methoxybenzyl isothiocyanate (24 mg, 0.14 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture was stirred at r.t. for 18 hours. 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid, purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions), and concentrated in vacuo to give the desired acid as a white solid.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.N([O-])=[O:15].[Na+].S([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>S(=O)(=O)(O)O>[OH:15][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCCCc2ccc(O)cc21
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
To a solution of 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.53 g) in 10% sulfuric acid (130 ml) was added sodium nitrite (4.9 g) and sodium sulfite (694 mg) under ice-cooling. After being stirred for 20 minutes at this temperature, to the reaction mixture was added toluene (100 ml), stirred at the room temperature for 18 hours and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.08 g).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N(C1CC1)C1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (56 mg, 0.2 mmol) was dissolved in DMF (2.5 ml) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 4-chloromethyl-biphenyl (81 mg, 0.4 mmol). The reaction mixture was stirred for 12 hours at 80° C. and the solvent was evaporated. The residue was purified by flash chromatography to give 16.4 mg of the desired product N-cyclopropyl-N-[1-(4-phenylbenzyl)piperidin-4-yl]benzenesulfonamide (16). 1H NMR (CDCl3): δ 7.92-7.85 (m, 1H), 7.63-7.31 (m, 9H), 7.30-7.25 (m, 4H), 3.93-3.83 (m, 1H), 3.54 (s, 2H), 3.00-2.89 (m, 2H), 2.14-1.89 (m, 5H), 1.66-1.49 (m, 2H+H2O), 1.04-0.97 (m, 2H), 0.81-0.72 (m, 2H). LC: 98%. MS (EI): m/z 447 (M+H+).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]([O:21][CH3:22])=[O:20])([O-])=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[NH2:6][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc2c([N+](=O)[O-])cccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cccc2c(N)cccc12
Temperature: 70 °C
Yield: 116.2 %

Procedure:
1 cm3 of 97% sulphuric acid is added to a suspension of 4.7 g of 5-nitro-1-naphthoic acid in 50 cm3 of methanol and the reaction mixture is then brought to reflux for 12 hours. The solution is cooled to a temperature in the region of 20° C. and the precipitate formed is filtered off by centrifuge and washed twice with 5 cm3 of ice-cold methanol and then dried to constant weight. 4.56 g of methyl 5-nitro-1-naphthoate are obtained, melting at 105° C. 21.5 g of tin(II) chloride dihydrate are added to a solution of 4.45 g of methyl 5-nitro-1-naphthoate in a mixture of 150 cm3 of ethyl acetate and 35 cm3 of ethanol. The solution is heated to a temperature in the region of 70° C. for 30 minutes and then cooled to a temperature in the region of 20° C. The reaction mixture is poured onto 200 cm3 of ice and the pH of the solution is progressively brought to 7-8 by addition of a 5% (w/v) sodium hydrogen carbonate solution. The mixture obtained is filtered on a sintered glass covered with Celite, the organic phase is separated by settling and the aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 4.5 g of methyl 5-amino-1-naphthoate are obtained in the form of an oil which are used in the following stage without other purification. 14.75 g of S-triphenylmethyl-N-(tert-butoxycarbonyl)cysteinal, 0.14 cm3 of concentrated acetic acid, molecular sieves (3Å) and then 4.15 g of sodium cyanoborohydride are added to a solution of 4.5 g of methyl 5-amino-1-naphthoate in 30 cm3 of methanol. The reaction mixture is stirred for 2 days at a temperature in the region of 20° C. and then filtered on sintered glass covered with Celite. The sintered glass is washed with methanol. The filtrate is concentrated under reduced pressure, redissolved in 150 cm3 of ethyl acetate and washed with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution, with 100 cm3 of a 10% (w/v) aqueous citric acid solution, with 100 cm3 of distilled water, with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution and finally with 100 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The product is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (85/15 by volume)]. 3.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate are obtained in the form of a beige foam which are used in the following stage without other purification.
Reaction SMILES: [C:1]([N:18](CC(C)C)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.CN(C=O)C>C(Cl)Cl>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:20]([OH:22])=[O:21])[CH2:4][CH:5]([CH3:17])[CH3:6]
Reactant: CC(C)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 5 h

Procedure:
FMOC-Leu*-Cl was prepared by dissolving FMOC—N-isobutylglycine (150 mg, 0.42 mmol) in CH2Cl2 (2.8 mL), and adding thionyl chloride (309 μL, 4.2 mmol) and 3 μL DMF (0.04 mmol). The reaction mixture was stirred for 5 hours and concentrated in vacuo., repeatedly dissolving in CH2Cl2 (3××) to provide FMOC-Leu*-Cl as a colorless oil (146 mg. 92%): IR (cm−1)-1804, 1720, 1715. FMOC-Phe*-Cl was similarly prepared.
Reaction SMILES: BrCC1C=CC(C2CCCN2C(OC(C)(C)C)=O)=CC=1.ClCC1C=CC(C2C=CC=CN=2)=CC=1.[Cl:35][C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]3[CH2:63][CH2:62][CH2:61][N:60]3C(OC(C)(C)C)=O)=[CH:55][CH:54]=2)[CH:38]=[C:39]2[C:44]=1[C:43](=[O:45])[N:42]([CH3:46])[C:41](=[O:47])[N:40]2[CH2:48][CH:49]([CH3:51])[CH3:50].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:36]1[N:37]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([CH:59]3[CH2:63][CH2:62][CH2:61][NH:60]3)=[CH:57][CH:58]=2)[CH:38]=[C:39]2[C:44]=1[C:43](=[O:45])[N:42]([CH3:46])[C:41](=[O:47])[N:40]2[CH2:48][CH:49]([CH3:51])[CH3:50]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(C4CCCN4C(=O)OC(C)(C)C)cc3)cc21
Agent: CC(C)(C)OC(=O)N1CCCC1c1ccc(CBr)cc1
Agent: ClCc1ccc(-c2ccccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(C4CCCN4)cc3)cc21

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 6 wherein tert-butyl 2-(4-(bromomethyl)phenyl)pyrrolidine-1-carboxylate is used in step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. The obtained tert-butyl 2-(4-((5-chloro-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrrolo[3,4-d]pyrimidin-6-yl)methyl)phenyl)pyrrolidine-1-carboxylate is deprotected with TFA in CH2Cl2 at room temperature to give 5-chloro-1-isobutyl-3-methyl-6-(4-(pyrrolidin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione, which is N-methylated with 37% formaldehyde aqueous solution and sodium borohydride in methanol at room temperature to give 5-chloro-1-isobutyl-3-methyl-6-(4-(1-methylpyrrolidin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione in a good overall yield. The obtained intermediate reacts with aniline using the procedure described in step 3 of EXAMPLE 6 to give pure product after HPLC purification. MS (ESI) m/z 486.3 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][N:12](C)C)=[CH:5][CH:4]=1.O.[NH2:17]N.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][N:17]=2)=[CH:5][CH:4]=1
Reactant: CN(C)CCC(=O)c1ccc(Cl)cc1
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc(C2=NNCC2)cc1
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 1-(4-chloro-phenyl)-3-dimethylamino-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50° C. The mixture was refluxed for 2 hours, and evaporated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic phase was washed twice with water, dried and evaporated under reduced pressure, to give 25.0 g of a yellow solid, m.p. 90-100° C.
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2Cl.[CH3:26][O:27][Na]>CO>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[O:27][CH3:26]
Reactant: CO[Na]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Solvent: CO
Product: COc1cc(Cn2cnc3c(OC)nc(N)nc32)c(Br)c(OC)c1OC

Procedure:
A solution of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (see example 51) in MeOH was treated with MeONa at reflux for 1 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 5.229 min. 1H-NMR (CDCl3): δ 7.69 (s, 1H), 6.58 (s, 1H), 5.33 (s, 2H), 4.88 (s, 2H), 4.11 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1.[NH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([NH:23][C:20]([C:18]2[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=2)=[O:22])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)on1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN2CCOCC2)on1
Yield: 68.6 %

Procedure:
As described for example 12b, 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (65 mg, 0.22 mmol) was converted, using 4-amino-morpholine (29 mg, 0.28 mmol) instead of N-aminopyrrolidine HCl, to the title compound (58 mg, 70%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=385.2 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[O:22][S:23]([OH:26])(=[O:25])=[O:24]>CO>[S:23]([O-:26])([O-:25])(=[O:24])=[O:22].[CH3:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[P:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH-:5]1
Reactant: Cc1ccccc1P(c1ccccc1)c1ccccc1
Reactant: NOS(=O)(=O)O
Solvent: CO
Product: Cc1ccccc1P1(c2ccccc2)(c2ccccc2)C=CC=C[CH-]1
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 115.3 %

Procedure:
A mixture of 9.2 g of diphenyl(2-methylphenyl)phosphine in 65 ml of methanol was heated to solution on a steam bath, then cooled to room temperature. Over 5 minutes, a solution of 3.76 g of hydroxylamine-O-sulfonic acid in 24 ml of methanol was added. This mixture was filtered into 400 ml of ether and the solid collected giving 8.40 g of P-(2-methylphenyl)-P,P-diphenylphosphine inide, sulfate salt.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].[CH3:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C(=O)NCc2ccc(Cl)c(C(=O)Nc3ncc[nH]3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Dissolve 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (100 mg, 0.35 mmol, 1.0 equiv) and 1-methylcyclopropanecarboxylic acid (45.3 mg, 0.45 mmol, 1.3 equiv) in DMF (0.697 mL), add triethylamine (82.5 μL, 0.59 mmol, 1.7 equiv) and BOP (231 mg, 0.52 mmol, 1.5 equiv). Stir the mixture at 60° C. overnight, and purify the crude mixture by flash chromatography on silica gel eluting with a 20% to 60% EtOAc/hexanes gradient. Recrystallize the material from EtOAc, filter, and wash with EtOAc to provide the title compound as a white solid (116 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 11.76 (br s, 2H), 8.13 (t, 1H, J=6.0 Hz), 7.43 (d, 1H, J=8.2 Hz), 7.39 (d, 1H, J=1.3 Hz), 7.29 (dd, 1H, J=8.2, 1.3 Hz), 6.74 (br s, 2H), 4.25 (d, 2H, J=6.0 Hz), 1.26 (s, 3H), 0.93 (app q, 2H, J=3.1 Hz), 0.50 (app q, 2H, J=3.2 Hz). MS (m/z) (35Cl/37Cl) 333/335 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>COCCO>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:18][CH:17]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: COc1ccc(C(=O)O)c(N)c1
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1ccc2c(O)ncnc2c1
Temperature: 130 °C
Reaction time: 15.25 h
Yield: 89.8 %

Procedure:
Step 1 A mixture of 2-amino-4-methoxybenzoic acid (0.5 g, 2.99 mmol) and formamidine acetate (0.623 g, 5.98 mmol) in 2-methoxyethanol (4 mL) was heated at 130° C. After 15.25 h, the mixture was cooled to rt. The resulting precipitate was collected by filtration, washed with methanol and dried to provide 7-methoxyquinazolin-4-ol as a tan solid (473 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (1 H, br. s.), 8.06 (1 H, s), 8.03 (1 H, d, J=9.5 Hz), 7.03-7.14 (2 H, m), 3.90 (3 H, s).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[H-].[Na+].Cl[C:7]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:23])[CH:13]=2)[N:8]=1.O>CN(C=O)C>[Cl:23][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:3][CH:1]=[O:2])[N:16]=[C:15]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a solution of 54 mg of dry formamide in DMF (5 ml) was added 48 mg of sodium hydride (60%), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), followed by warming to 85° C. and further stirring for 3 hours. The resulting reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The extract was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 64 mg of the titled compound. Mp.252.1° C. 1H NMR: 7.59-7.66 (3H, m), 7.72-7.81 (3H, m), 7.88 (1H, d, J=8.8 Hz), 8.02 (1H, d, J=2.0 Hz), 8.37 (1H, br. d, J=10.4 Hz), 9.71 (1H, d, J=10.4 Hz).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[CH:36][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][NH:21][CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[CH:36][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3cnc(Nc4ccc5c(n4)CCNC5)nc3n(C3CCCC3)c2cn1
Yield: 80.5 %

Procedure:
A solution of tert-butyl 2-((9-cyclopentyl-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (217 mg, 0.477 mmol) in TFA/DCM (1:1, 2 mL) was stirred at room temperature for 30 minutes and then concentrated. The residue was purified by flash chromatography on silica gel eluting with 25% to 75% solvent A (DCM:MeOH:NH4OH, 100:10:1) in DCM to give the title compound as a yellow solid (148 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ 1.87-1.90 (2H, m), 2.14-2.21 (4H, m), 2.43-2.47 (2H, m), 2.89 (2H, t, J=5.0 Hz), 3.26 (2H, t, J=5.0 Hz), 4.02 (2H, s), 5.36 (1H, m), 7.41 (1H, d, J=10.0 Hz), 7.85 (1H, d, J=5.0 Hz), 8.19 (1H, br. s), 8.31 (1H, d, J=10.0 Hz), 8.52 (1H, d, J=5.0 Hz), 8.91 (1H, s), 9.11 (1H, s) ppm; LCMS m/z: 386 (M+1).