Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17]N.Br>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[C@@H:3]([CH3:4])[OH:20].[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][CH2:2][NH2:1].[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: NCCC[C@H](N)C(=O)O
Agent: Br
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
30 mg. of the tetrapeptide resin are hydrolyzed with 6 N hydrochloric acid in dioxane for 18 hours and the product assayed on the amino acid analyzer. It yields a ratio of Thr 1, Lys 1, Pro 1, Arg 1. The value for Arg is the sum of Arg, Orn and nitro Arg. The tetrapeptide is cleaved off the resin with hydrogen bromide in TFA at room temperature for 1- 1/2 hours. It is then dried in vacuo, washed twice with water and lyophilized. Its weight of 176 mg. represents a 78% yield based on Lys. It is then taken up in 10 ml. of methanol containing 10% acetic acid. This is then exposed to catalytic hydrogenation with twice its weight 350 mg. of palladium on barium sulfate in a hydrogen atmosphere at 60 pounds per square inch pressure with continuous shaking for 24 hours at which time no nitro Arg is detected at 271 mμ, the peak of absorption. An aliquot is again hydrolyzed with 6 N HC1 in water and assayed. This yields a comparable figure for Thr, Lys, Pro, and Arg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH2:11][OH:12])[CH:3]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1.O>C(Cl)Cl>[Si:17]([O:12][CH2:11][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(CO)ncc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-methyl-5-nitropyridin-2-yl)methanol (1.2 g, 7.1 mmol) in 5 mL of CH2Cl2, were added tert-butylchlorodiphenylsilane (2.0 g, 7.1 mmol) and imidazole (0.049 g, 0.71 mmol) at an ambient temperature. The reaction was stirred at 25° C. for 2 hrs. The reaction was poured into H2O, extracted with ethyl acetate, and dried over MgSO4. The ethyl acetate was concentrated under vacuum and purified over SiO2 to afford the desired compound 2-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-5-nitropyridine in 90% (2.6 g). 1HNMR (CDCl3, 400 MHz) δ 1.12 (s, 9H), 2.78 (s, 3H), 4.85 (s, 2H), 7.21 (s, 1H), 7.24˜7.89 (m, 10H), 9.15 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.ClCCl>C(=O)([O-])[O-].[Na+].[Na+].CN1CCCC1=O.O>[S:18]1[CH:22]=[CH:21][C:20]([C:2]2[N:7]=[C:6]([S:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:19]1
Reactant: O=S(=O)(Oc1ccccc1)c1cccc(Br)n1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1ccccc1)c1cccc(-c2ccsc2)n1
Temperature: 130 °C

Procedure:
A mixture of phenyl 6-bromo-2-pyridinesulfonate (D7) (1.0 g, 7.2 mmol), 3-thienylboronic acid (532 mg, 8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) complex with dichloromethane (80 mg) in sodium carbonate (2M solution, 5 ml) and 1-methyl-2-pyrrolidinone (8 ml) was heated at 130° C. in a microwave reactor for 5 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (1:40 to 1:5 ethyl acetate:hexanes) to afford the title product (D8). MS (ES+) m/e 318 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:7]=1.CCN(CC)CC.C[CH2:41][O:42][C:43](C)=[O:44]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:41][O:42][C:43](=[O:44])[C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:17]=2)[CH3:31])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of N-[4-(5-chloro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (160 mg, 338 μmol, example 82) in MeOH (1.2 mL) and EtOAc (1.2 mL) was added PdCl2(dppf)-CH2Cl2 complex (31.8 mg, 38.9 μmol, CAS RN 851232-71-8) and NEt3 (51.4 mg, 70.7 μL, 508 μmol). The reaction mixture was stirred at 150° C. at 70 bar under CO atmosphere for 24 hours. The reaction mixture was treated with silica gel and directly purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow oil (39 mg, 23%). MS (ESI): m/z=497.129 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[OH:15][CH2:14][C@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@H]1C[C@@H](O)CN1
Reaction time: 16 h

Procedure:
To tert-butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (498.5 mg, 2.29 mmol) dissolved in DCM (6.8 mL) was added TFA (0.85 mL). The mixture was stirred for 16 hours. The mixture was concentrated to give (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol as a TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1C=CC=CC=1.O1CCCC1.CN(C)C1C=CN=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12]2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(C(=O)Nc3ccc(Cl)cc3)c3ncccc23)cc1OC
Temperature: 200 °C
Yield: 39.8 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine 1 (40 mg, 0.16 mmol) was dissolved in benzene and 4-chlorophenyl isocyanate (36 mg, 0.24 mol) dissolved in tetrahydrofuran (4 mL) was added. 4-Dimethylaminopyridine (20 mg, polymer bound) was added. The reaction was heated in a CEM Discover microwave at 200° C. for 10 minutes. The mixture was filtered and concentrated. The resulting solid was washed with a minimum of methanol, filtered, and then washed with dichloromethane to provide 26, (26 mg, 40%). MS(ESI) [M+H+]+=408.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C1COCC1.C(O)(=O)C>[O:1]1[CH:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]2[CH:3]=[C:2]1[CH2:10][NH:13][CH3:12]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CNCC1=CC2C=CC=CC2O1
Yield: 64 %

Procedure:
To a stirred solution of benzofuran-2-carboxaldehyde (1.50 g) and 4 Å molecular sieves in dichloroethane (50 ml) under an atmosphere of nitrogen was added methylamine in THF (2.0M, 10.3 ml) and acetic acid (1.23 g). Stirring was continued for 2 h before sodium triacetoxyborohydride (2.18 g) was added and stirring as continued overnight. The mixture was filtered, absorbed onto silica gel and chromatographed eluting with dichloromethane/methanol (9:1) to yield the title compound (1.05 g, 64%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OCc1cnc2ccc(Cl)nn12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3 g, 7.1 mmol) in DCM (50 mL) was added active MnO2 (3 g, 34.5 mmol). The mixture was stirred at rt overnight and filtered. The filtrate was concentrated under vacuum and the residue was washed with EtOAc to afford 6-chloro-imidazo[1,2-b]pyridazine-3-carbaldehyde (0.7 g) in 54% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 10.36 (s, 1H), 8.42 (s, 1H), 8.08 (d, 1H), 7.38 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:35])[CH:18]([N:25]4[C:29]([CH3:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]4)[CH2:19][C:20]([O:22]CC)=[O:21])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O[Li].O.C1COCC1.Cl>O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:35])[CH:18]([N:25]4[C:29]([CH3:30])=[CH:28][C:27]([C:31]([F:32])([F:34])[F:33])=[N:26]4)[CH2:19][C:20]([OH:22])=[O:21])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)cc1C
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1C(CC(=O)O)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
A mixture of ethyl 4-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-4-oxo-butanoate (0.030 g, 0.060 mmol), LiOH.H2O (0.020 g, 0.47 mmol), THF (0.4 mL), MeOH (0.4 mL) and H2O (0.2 mL) was stirred for 30 min at rt. It was then acidified with 1 M aq. HCl (2 mL) and extracted with IPA/CHCl3 (1:2, 50 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to yield 4-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-4-oxo-butanoic acid (0.029 g, 100%).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.[CH2:39](I)[CH3:40]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH2:39][CH3:40])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: CCI
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC1CCCCC1)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (52 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (35 mg, yield 93%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH2:27])[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)[N:19]=2)=[CH:14][C:13]=1[O:41][CH3:42]>N1C=CC=CC=1>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[O:8])=[C:13]([O:41][CH3:42])[CH:14]=3)[C:26]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: Cc1noc(C)c1C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1c(C)noc1C
Reaction time: 5 h

Procedure:
3,5-Dimethyl-4-isoxazolecarbonyl chloride (22 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was re-crystallized from DMSO to give cis-N4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3,5-dimethyl-4-isoxazolecarboxamide (33 mg, 87%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.24 (m, 2H), 2.36 (m, 2H), 2.41 (s, 3H), 2.63 (s, 3H), 2.77 (m, 3H), 3.17 (s, 3H), 3.37 (bm, 8H), 3.95 (s, 3H), 4.95 (m, 1H), 7.37 (m, 2H), 8.17 (d, J=8.17, 1H), 8.30 (s, 1H), 9.26 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.), MH+ =560.2, Rt=2.44 min.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[N+:33]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[NH2:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a mixture of 8.6 g of iron powder, 27 ml of acetic acid, and 2.7 ml of water was added dropwise a solution of 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 23 ml of acetic acid, while the temperature of the reaction mixture was kept at 35° C. or lower. After completion of the dropwise addition, the reaction mixture was stirred for 2 hours and then filtered through Celite. The filtrate was diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.BrCl>>[Br:7][C:5]1[CH:6]=[C:2]([C:22]#[C:21][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: ClBr
Product: Clc1ccc(-c2ccc(C#Cc3cc(Br)cs3)nc2)cc1

Procedure:
The product was obtained analogously to Example 7.1e starting from 2,4-dibromothiophene and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.78 g (50% of theoretical); C17H9BrClNS (M=374.683); calc.: molpeak (M+H)+: 374/376/378 (BrCl); found: molpeak (M+H)+: 374/376/378 (BrCl); HPLC-MS: 7.40 minutes (method B).
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:22])=O>>[ClH:22].[Cl:22][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cl
Product: Clc1ncnc2nc[nH]c12
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 50 g (0.368 mole) of hypoxanthine, 120 ml. of N,N-dimethylaniline and 500 ml. of phosphorus oxychloride was refluxed for 20 minutes. Excess phosphorus oxychloride was removed by vacuum distillation with an external oil bath having a temperature below 70° C. and 1.0 liter of methylene chloride was added to the red oily residue. The red methylene chloride solution was cooled in an ice water bath and hydrogen chloride gas was bubbled through the solution until the solution turned a bright yellow color. After stirring the reaction mixture overnight, nitrogen was passed through the solution for 1.5 hours to remove excess hydrogen chloride. The product was collected by filtration, washed with two 150 ml. portions of hot methylene chloride and dried to give 59.3 g (99% yield) of 6-chloropurine hydrochloride, as a cream colored solid, λ max (H2O)=264 nm, ε=9.32×103.
Reaction SMILES: CC1(C)C(C)(C)OB(C2[C:10]([NH:15][C:16](=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.BrC1C=CC=CC=1C#[N:28].C(=O)([O-])[O-].[Na+].[Na+].[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)C>CO>[CH:14]1[CH:13]=[CH:12][N:11]=[C:10]2[C:45]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:16]([NH2:28])=[N:15]2
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Nc1nc2ncccc2c2ccccc12
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (1.0 eq.) and 2-bromobenzonitrile (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give benzo[c][1,8]naphthyridin-6-amine as a white solid. 1H NMR (methanol-d4): δ 8.88 (dd, 1H), 8.67-8.63 (m, 2H), 8.30 (d, 1H), 7.90 (dt, 1H), 7.74 (dt, 1H), 7.36 (dd, 1H). LRMS [M+H]=196.1
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N+:5]([O-])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:15])C>>[OH:15][CH:7]1[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1cc[n+]([O-])c2c1CCCC2
Reactant: CC(=O)OC(C)=O
Product: Cc1ccnc2c1CCCC2O
Temperature: 25 °C

Procedure:
A solution of the crude product of Step 1 (19.2 g, 115 mmol) in acetic anhydride (100 ml) was heated at 110° for lh, cooled to room temperature, and evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solution treated with 4N-NaOH (100 ml). After 2h, the solution was concentrated in vacuo and the aqueous residue partitioned between dichloromethane (100 ml) and water (100 ml). The chlorinated phase was dried (Na2SO4), and evaporated in vacuo to give an oil which was purified by chromatography (silica; ether) to give the product as crystals (12.0 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH:25]3[S:29][CH2:28][CH2:27][S:26]3)([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=2[O:30][CH3:31])[C@@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C.[ClH:38].CO>CCOC(C)=O>[ClH:38].[ClH:38].[CH3:31][O:30][C:17]1[CH:18]=[CH:19][C:20]([C:22]([CH:25]2[S:26][CH2:27][CH2:28][S:29]2)([CH3:24])[CH3:23])=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
To a solution of Compound 82 (0.128 g) in EtOAc (5 ml) was added an excess amount of 10% HCl-MeOH (1 ml) for 8 hr. The resulting precipitate was collected and washed with EtOAc to give Compound 83 (0.069 g) as a colorless crystal.
Reaction SMILES: [F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].Br[CH2:26][C:27]1[S:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6])[C:14]1[CH:15]=[C:16]2[C:20]([CH2:19][CH2:18][CH2:17]2)=[CH:21][C:22]=1[O:23][CH2:26][C:27]1[S:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1
Reactant: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Reactant: CCOC(=O)c1cnc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(COc2cc3c(cc2N(C[C@H](C)F)S(=O)(=O)c2nc(C)cs2)CCC3)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
137 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide was dissolved in 1.05 mL of DMF, and 139 mg of ethyl 2-(bromomethyl)-1,3-thiazole-5-carboxylate and 102 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 2 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 154 mg of ethyl 2-{[(6-{[(2S)-2-fluoropropyl][(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-1,3-thiazole-5-carboxylate.