Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:24][C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:26]=1[NH2:27]>CC(C)=O.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:27][C:26]2[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:25]=2[CH3:24])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Cc1cccc(C)c1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C)c1NC(=O)c1ccc(Cl)nc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A slurry of 25 g of 6-chloronicotinic acid in approximately 300 ml of acetone was treated with 22.6 ml of triethylamine. The reaction mixture was cooled to approximately -10° C. by means of an external ice/methanol bath. A solution of 15.5 ml of ethyl chloroformate in acetone was added to the mixture at a rate to maintain the temperature below 0° C. After stirring with the cold bath for 2 hours, a solution of 38.5 g of 2,6-dimethylaniline in approximately 150 ml of acetone was added while maintaining the temperature below 0° C. After the addition was complete, the mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted into ethyl acetate. The organic layer was washed with water, dilute hydrochloric acid, water, a dilute sodium bicarbonate solution, water (twice), and a saturated sodium chloride solution. The organic solution was dried over sodium sulfate and concentrated in vacuo to provide 30.5 g of a solid. Crystallization from methanol/water provided 14.6 g of the desired title product, m.p. 165°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][CH2:24][CH2:25][CH3:26])[CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN.O>C(O)C>[CH2:24]([O:23][N:22]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:10][NH2:11])[CH2:25][CH3:26]
Reactant: CCCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCON=C(CN)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To 235 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(propoxyimino)ethyl]phthalimide in 5 ml of ethanol, 90 mg of hydrazine monohydrate was added and refluxed with heating for 3 hours with stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 20 ml of water and extracted with ethyl acetate (35 ml×2). The resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 151 mg of the desired crude product as a brown oil. The oil was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCCl.CCOCC>[CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl (S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate (0.23 g, 0.9 mmol) in 1,2-dichloroethane (5 mL), was added Dess-Martin periodinane (0.49 g, 1.34 mmol). The resulting mixture was heated in a CEM microwave synthesizer at 70° C. for 3 min, diluted with ether (100 mL), and washed with 1 N NaOH (2×10 mL). The ether layer was dried over Na2SO4, and the solvent was removed in vacuo to give (S)-tert-butyl 1-cyclohexyl-3-oxopropan-2-ylcarbamate as an oil. MS ESI+ve m/z 256 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+]>O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ccnc2cccnc12
Reactant: CC(C)(C)c1ccc(CCN)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(CCNc2ccnc3cccnc23)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A mixture of 500 mg of 4-chloro-1,5-naphthyridine and 1.0 g of N-[2-[4-(t-butyl)phenyl]ethyl]amine was stirred at 130° C. for 30 minutes. Then a 50/50 mixture of ammonium hydroxide and water was added. The product was extracted into methylene chloride, which was then concentrated. The product was purified by HPLC (silica gel, 20% ethyl acetate/80% pentane). The fractions containing the major product were collected and concentrated giving 0.277 mg of the title product as an oil. Yield 30%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:16]C(=O)C(OCC)=O)=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[NH:6][C:5](=[O:24])[C:4]1=[O:25])[CH3:2].O.C(O)C>S(=O)(=O)(O)O>[NH2:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5](=[O:24])[NH:6]2
Reactant: CCOC(=O)C(=O)Nc1cc2[nH]c(=O)c(=O)n(CC)c2cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCn1c(=O)c(=O)[nH]c2cc(N)c([N+](=O)[O-])cc21
Yield: 94.4 %

Procedure:
24 g (68.6 mmol) of this amide were refluxed in a mixture of 13 ml of concentrated sulfuric acid, 240 ml of water and 250 ml of ethanol for 3 h. The precipitate was then filtered off with suction to yield 16.2 g (98%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=3)=[N:9][N:8]([CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CN(C)c1ccc(Cc2n[nH]c3ncc(Br)cc23)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Cc2nn(COC(=O)C(C)(C)C)c3ncc(Br)cc23)cc1
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
[4-(5-Bromo-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-phenyl]-dimethyl-amine (500 mg, 1.51 mmol) and N,N-dimethylformamide (40 ml) was stirred at room temperature. Sodium hydride (60%, 121 mg, 3.03 mmol) was added to the mixture, and the reaction mixture was stirred for 30 minutes. Chloromethyl pivalate (0.44 ml, 3.05 mmol) was added, and the reaction mixture was stirred for 1.5 hours at room temperature. Saturated aqueous ammonium chloride solution was added and the mixture extracted with dichloromethane. The crude material was purified by flash chromatography (0 to 100% ethyl acetate in hexanes) to give 517 mg (77%) of 2,2-dimethyl-propionic acid 5-bromo-3-(4-dimethylamino-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. MS m/z 445.2, 447.2 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([N:11]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:12]1[CH:39]=[CH:38][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=[CH:21][C:20]=2[NH:30]C(=O)OC(C)(C)C)=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:11]([CH2:40][CH2:41][N:42]([CH3:43])[CH3:44])[C:12]1[CH:39]=[CH:38][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=[CH:21][C:20]=2[NH2:30])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)N(CCN(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(CCN(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reaction time: 0.75 h

Procedure:
TFA (0.5 mL) was added to the tert-butyl [2-[(4-{acetyl[2-(dimethylamino)ethyl]amino}benzoyl)amino]-4-(2-thienyl)phenyl]carbamate (0.05 g, 0.096 mmol) in DCM (1 mL). The reaction mixture was stirred for 45 min. LC/MS shows mass for the product. The mixture was concentrated and 1H NMR was taken to show pure compound. 1H NMR (600 MHz, MeOH-d4) δ 8.20 (d, J=8.4 Hz, 2H), 8.69 (d, J=1.8 Hz, 1H), 7.65 (dd, J=2.0, 8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.43 (dd, J=4.3, 7.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.11 (dd, J=3.7, 5.1 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 3.31-3.34 (m, 2H), 3.00 (s, 6H), 1.92 (s. 3H); MS: cal'd 423 (MH+), exp 423 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)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.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([N:53]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])[C:54]3([C:59]([OH:61])=O)[CH2:58][CH2:57][CH2:56][CH2:55]3)(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C)C=O>[CH3:67][O:66][C:64](=[O:65])[CH2:63][CH2:62][N:53]([C:54]1([C:59](=[O:61])[NH:77][O:76][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:55][CH2:56][CH2:57][CH2:58]1)[S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=2)=[CH:45][CH:46]=1)(=[O:51])=[O:52]
Reactant: COC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C1(C(=O)NOCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 85.7 %

Procedure:
Diisopropylethylamine (4.3 mL, 24.6 mmole) and (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (11.0 grams, 24.9 mmole) were added sequentially to a solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)-amino]cyclopentane-1-carboxylic acid (10.1 grams, 22.4 mmole) in N,N-dimethylformamide (170 mL). The mixture was stirred for 4 hours. Additional diisopropylethylamine (7.8 mL, 44.6 mmole) and O-benzylhydroxylamine hydrochloride (4.64 grams, 29.1 mmole) were then added and the resulting mixture was stirred at 60° C. for 16 hours. After concentration under vacuum, the residue was taken up in water and acidified with 1 N aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate and the extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give a solid which upon trituration with 7:3:1 hexane/ethyl acetate/methylene chloride provided 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester as a white crystalline solid (10.65 grams, 86%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.CC([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=O)(C)C>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:1]3[C:35](=[O:36])[CH2:34][NH:33][C:31]3=[O:30])[N:4]=2)=[O:10])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CN3C(=O)CNC3=O)cs2)c(C(=O)C2CCCC2)c1
Yield: 22.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2,5-dioxo-imidazolidin-1-ylmethyl)-thiazol-2-yl]-urea (78 mg, 69%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (358 mg, 1.0 mmol) and t-Boc-glycine (90 mg, 0.80 mmol) following the general procedure U.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:3][CH:4]=1
Reactant: O[C@@H]1CCOC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(O[C@@H]2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and (R)-3-hydroxytetrahydrofuran by the method of Example 10 (b).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([N:20]=[O:21])[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Agent: [Na+]
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2.0 g (7.7 mmol) of 6-amino-1-benzyl-3-propyluracil are heated to B0° C. in 15 ml of water and mixed with a solution of 0.55 g of sodium nitrite in 3 ml of water. After the addition of 1 ml of glacial acetic acid-a red solid is precipitated. The pH is adjusted to 4 and the suspension is stirred for a further 30 minutes at 80° C. After cooling, the crystals are filtered under suction and washed with water. 1.9 g of the title compound are obtained in the form of reddish-violet crystals (86% of theory), m.p. 208°-212° C./decomposition.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28](OCC)=[O:29])([C:23](OCC)=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([CH2:23][OH:24])([CH2:28][OH:29])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)(CC1CCN(Cc2ccccc2)CC1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC(CO)(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Yield: 57.7 %

Procedure:
A mixture of 430 mg (1.0 mmol) of 1-benzyl-4-(3-phenyl-2,2-bis(carboethoxy)propyl)piperidine (from EXAMPLE 32, Step D) and 65 mg (1.7 mmol) of lithium aluminum hydride was heated at reflux for 1 h. The reaction was cooled and quenched with 10 mL of 1.0 N NaOH. The quenched mixture was partitioned between 50 mL of ether and 25 mL of H2O and the layers were separated. The organic layer was dried over MgSO4 and concentrated. The resulting solid was triturated with ether, filtered and dried to afford 204 mg (59%) of the title compound: 1H NMR (500 MHz) δ 1.16 (d, J=5.0,2H), 1.32-1.36 (m, 2H), 1.45-1.49 (m, 1H), 1.66 (d, J=12.0, 2H), 1.76 (br s, 2H), 1.97 (app t, J=11.5, 2H), 2.40 (br s, 2H), 2.73 (s, 2H), 2.83 (app d, J=11.5, 2H), 3.48 (s, 2H), 3.58 (ABq, J=10.5, 4H), 7.19-7.31 (10H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C=O)C>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[S:22][CH:21]=[N:20][C:19]=2[CH3:18])[CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1ncsc1N1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncsc1N1CCN(C(=O)/C=C/C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (33 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 4-methyl-5-piperazin-1-yl-thiazole dihydrochloride (38 mg, 0.15 mmol) and N-ethyl-N,N-diisopropylamine (0.7 mmol, 120 μl) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for three hours. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 32 mg of a solid (0.09 mmol, 70%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)(=[O:3])[NH2:2].[ClH:16].O1CCOCC1>>[ClH:16].[NH:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCCN1
Yield: 104 %

Procedure:
To (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (29.8 g, 139 mmol) was added a solution of 4N HCl in dioxane (209 mL, 836 mmol) and the resultant mixture stirred at room temperature for 18 hrs. The mixture was then concentrated and triturated with diethyl ether then vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the title product as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)nc1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a (0° C.) cooled and stirred solution of 2-bromo-5-aminopyridine (2.0 g, 11.56 mmol, 1.0 eq) in DCM (25 mL) was added sequentially 2,6-difluorobenzoyl chloride (1.44 mL, 11.56 mmol, 1.0 eq) and pyridine (1.19 mL, 13.87 mmol, 1.2 eq). The resulting mixture was allowed to warm to room temperature and then stirred at the same temperature for 30 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7](Cl)[N:6]=1)=[O:4].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(Cl)c(F)c1Nc1ccccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc(C#C[Si](C)(C)C)c(Cl)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5,6-dichloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), TMS-acetylene (1.20 equivalents), Pd(PPh3)2Cl2 (0.10 equivalents), CuI (0.10 equivalents), and i-Pr2NH (2.00 equivalents) in THF is stirred for 16 hours at room temperature. THF is evaporated in vacuo. The reaction mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl and brine. The organic layer is dried over MgSO4, filtered, and concentrated to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH2:1]([NH:4][C:11]([C:9]1[S:10][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute TUE is admixed dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).
Reaction SMILES: [OH:1][CH:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][CH:3]1[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.[BH4-].[Na+].O.C(=O)([O-])O.[Na+]>CO.Cl>[OH:12][CH:11]1[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][CH:3]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[CH:2]1[OH:1]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)C(O)C(c1ccsc1)N3
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)C(O)C(O)C(c1ccsc1)N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
50 mg of 8-hydroxy-2,3-dimethyl-9-(3-thienyl)-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 5 ml of methanol and treated with 100 mg of sodium borohydride at room temperature with vigorous stirring. After stirring at room temperature for 1 hour, the solvent is stripped off in vacuo, the residue is covered with a layer of 5 ml of water, the mixture is adjusted to pH 1 with a few drops of semisaturated aqueous hydrochloric acid and then adjusted to pH 8 using saturated aqueous sodium hydrogen carbonate solution, extracted three times with 20 ml of methylene chloride each time, the combined organic phases are concentrated to dryness in vacuo and the remaining solid residue is purified on silica gel (eluent: methylene chloride/methanol=13/1). 45 mg of the title compound of m.p. 134–38° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15]C(=O)C(C)(C)C)[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.C(O)(=O)C>[OH-].[Na+]>[NH2:15][C:10]1[NH:9][C:8](=[O:22])[C:7]2[C:6]3[CH:23]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Temperature: 75 °C

Procedure:
A solution of N-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)-pivalamide (0.15 g, 0.4 mole) in 0.75N NaOH (7 ml) was stirred and heated to 75° C. under a nitrogen atmosphere for 10.5 hours. The solution was cooled and made slightly acidic with acetic acid to cause precipitation of the product. The precipitate was collected, washed successively with water, methanol and ether, and dried to give 3-amino-9-bromobenzo[f]quinazolin 1(2H)-one as an off-white solid. (0.115 g, 99%) 1H NMR(DMSO-d6, 200 MHz) δ: 6.64(br s, 2H, NH2); 7.31(d, J=8.8 Hz, 1H, Ar); 7.57(dd, J=8.5, 1.9 Hz, 1H, Ar); 7.83(d, J=8.6 Hz, 1H, Ar); 8.02(d, J=9.0 Hz, 1H, Ar); 9.83(s, 1H, Ar); 11.28(br s, 1H, NH).
Reaction SMILES: [C:1]([Si:5]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][NH:15][C:13]=2[N:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CI.[C:21]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:5]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][N:15]([CH3:21])[C:13]=2[N:14]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Yield: 101.1 %

Procedure:
2-(t-Butyl-dimethyl silyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII) (700 mg, 2.5 mmol), 0.18 mL (3.5 mmol) of methyl iodide in DMF (10 mL), and K2CO3 (552 mg, 4 mmol) were reacted at ambient temperature for 15 h. After addition of H2O (10 mL), the reaction was extracted with EtOAc (100 mL), and the organic layer was washed with a brine solution (10 mL), and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIII) (750 mg, 100%) as a light yellow oil. LCMS (ESI) m/z=297 (M+H)+.