Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[C:5]([Cl:17])=[N:4][N:3]=1.C(N(CC)CC)C.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C1COCC1.C(O)C>[Cl:17][C:5]1[C:6]2[C:11]3[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=3[N:9]=[CH:8][C:7]=2[C:2]([N:29]2[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]2)=[N:3][N:4]=1
Reactant: OC1CCNCC1
Reactant: CCn1ncc2c3c(Cl)nnc(Cl)c3cnc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1ncc2c3c(Cl)nnc(N4CCC(O)CC4)c3cnc21
Temperature: 60 °C
Yield: 80 %

Procedure:
To a suspension of 6,9-dichloro-3-ethyl-3H-pyrazolo[4′,3′:5,6]pyrido[3,4-d]pyridazine (3.2 g, 12.0 mmol) in THF/ethanol (40 mL, 1:1) in a 100 mL pressure tube was added triethylamine (5 eq) and 4-hydroxy-piperidine (1.1 eq) sequentially. The reaction mixture was heated in an oil bath at 60° C. for 2 h. The progress of the reaction was monitored by HPLC. The reaction mixture was transferred to a 200 mL round-bottomed flask, and the solvent was removed via evaporation under reduced pressure. The light brown residue was resuspended in saturated sodium bicarbonate (100 mL), and the precipitated solid was collected by filtration. This orange solid was washed thoroughly with water and dried in a vacuum oven at 40° C. over night to afford the title compound (3.2 g, 80% yield). This material was >93% pure and was used directly without further purification.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:15])=O>ClCCl>[CH2:1]([C:5]1[C:9]([CH2:10][Cl:15])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1noc(C)c1CO
Solvent: ClCCl
Product: CCCCc1noc(C)c1CCl
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of (3-butyl-5-methyl-isoxazol-4-yl)-methanol (1.00 g, 5.9 mmol) in dichloromethane (10 mL) was added thionyl chloride (1.41 g, 11.8 mmol) dropwise at 0° C. After 1 h, the reaction mixture was evaporated to afford the title compound (980 mg, 88%) as a light brown liquid. MS: m/e=208.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([F:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[CH2:16](OCC)C>C(O)=O.C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([F:14])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOCC
Reactant: Fc1cc(F)cc(C2(F)CCNC2)c1
Agent: C=O
Solvent: O
Solvent: O=CO
Product: CN1CCC(F)(c2cc(F)cc(F)c2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-(3,5-difluorophenyl)-3-fluoropyrrolidine (0.17 g, 0.85 mmol) in formic acid (2.45 mL) and aqueous formaldehyde (40%, 2.2 mL) was heated at 85° C. for 1 h. Water (100 mL) and diethyl ether was added, the phases were separated and the aqueous phase was basified by the addition of aqueous sodium hydroxide (5M, 20 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.12 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 128-129° C.; MS m/z (relative intensity, 70 eV) 215 (M+, bp), 194 (29), 193 (36), 151 (33), 57 (92).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32]CC)=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:39]>CO.O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O-:32])=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C([O-])COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 3-{[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-yl]methyl}phenoxyacetate (353 mg) in MeOH:1,4-dioxane (1:1, 10 mL) was added 1N NaOH solution (0.744 mL) at 5° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated and Et2O was added thereto. The resulting solid was collected by filtration to give sodium 3-[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-ylmethyl]phenoxyacetate (327.7 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[S:26][C:27]([CH2:31][NH2:32])=[C:28]([CH3:30])[N:29]=1.O>C(#N)C>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH2:31][C:27]4[S:26][C:25]([CH3:24])=[N:29][C:28]=4[CH3:30])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: Cc1nc(C)c(CN)s1
Solvent: CC#N
Solvent: O
Product: COc1cc2c(NCc3sc(C)nc3C)c(C(N)=O)cnc2cc1-c1c(C)noc1C

Procedure:
To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 0.5 g,) in acetonitrile (50 ml) was added a solution of [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (0.64 g, dihydrochloride available from Matrix Scientific) in acetonitrile (10 ml). The reaction mixture was heated at reflux for 3 h, whereupon another portion of amine (0.5 g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2SO4 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7-(3,5-dimethyl-4-isoxazolyl)-4-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (0.33 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].[F-].[K+].CC#N>CCOC(C)=O.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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([F:23])([F:24])[F:22])=[C:15]([F:14])[CH:16]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(C(F)(F)F)c(F)c2)n1
Temperature: 115 °C
Yield: 70.3 %

Procedure:
To a 5 mL microwave vial was added methyl 4-amino-6-chloro-5-fluoropicolinate (500 mg, 2.44 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (851 mg, 2.93 mmol), potassium fluoride (KF; 369 mg, 6.35 mmol), and PdCl2(PPh3)2 (172 mg, 0.24 mmol). Subsequently, CH3CN (3.0 mL) and H2O (3.0 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave at 115° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×2 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes to yield the title compound as a yellow solid (570 mg, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dt, J=12.3, 6.2 Hz, 3H), 7.52 (d, J=6.4 Hz, 1H), 6.80 (s, 2H), 3.86 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −59.96, −59.99, −115.69, −144.18, −144.20; ESIMS m/z 333.21 ([M+H]+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>ClCCl>[CH2:30]([O:29][CH2:28][O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClCOCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.12 g, 8.65 mmol) and N,N-diisopropylethylamine (3.01 mL, 17.3 mmol) in dichloromethane (30 mL) was added benzyl chloromethyl ether (2.71 g, 17.3 mmol). After stirring at room temperature for 18 h, the mixture was poured into water. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:4 to 1:3) to give 2.29 g (72%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:6][CH:7]=1.CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1.[NH3:25]>CO>[NH2:25][C:17]1[C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:5]2[C:4]([CH3:14])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[N:20][S:19](=[O:24])[N:18]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: Cc1cc(Br)cnc1NCCCCN
Reactant: N
Solvent: CO
Product: Cc1cc(Br)cnc1NCCCCNC1=NS(=O)N=C1N
Reaction time: 2 h
Yield: 45 %

Procedure:
4-(5-Bromo-3-methylpyrid-2-ylamino)butylamine (0.7 g) in methanol was reacted with 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.44 g) overnight at room temperature. Methanolic ammonia (25 ml) was added and the reaction mixture was stirred for 2 hours. After evaporation, the residue was recrystallised from a mixture of acetonitrile and ether to yield 4-amino-3-[4-(5-bromo-3-methylpyrid-2-ylamino)-butylamino]-1,2,5-thiadiazole-1-oxide (0.45 g, 45%) m.p. 212°-214° C. dec.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:21])[CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:22])[C:9]=2[C:8]([NH:23][CH2:24][CH2:25][NH2:26])=[CH:7][CH:6]=1.[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[OH:21][C:12]1[C:11]2[C:10](=[O:22])[C:9]3[C:18](=[C:5]([NH:4][CH2:3][CH2:2][N:1]=[CH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:6]=[CH:7][C:8]=3[NH:23][CH2:24][CH2:25][N:26]=[CH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:19])[C:16]=2[C:15]([OH:20])=[CH:14][CH:13]=1
Reactant: NCCNc1ccc(NCCN)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Reactant: Cc1ccccc1
Reactant: O=Cc1ccccc1
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN=Cc3ccccc3)ccc(NCCN=Cc3ccccc3)c21
Reaction time: 312 h

Procedure:
A suspension of 2.00 g (0.0057 mole) of the free base, 1,4-bis[(2-aminoethyl)amino]-5,8-dihydroxyanthraquinone (prepared as described in Example 1) in 60 ml of toluene containing 1.82 g (0.0171 mole) of benzaldehyde was stirred and heated under reflux for 4 hours, using a Dean-Stark trap to remove by-product water. The hot reaction mixture was filtered to remove some residual solid which was washed with a minimal amount of toluene. The combined filtrate and wash was allowed to stand at room temperature for 13 days. The solid formed was collected by filtration and washed with a minimum of ether to yield 1.80 g of the product of the Example as a dark blue solid, mp 174°-179° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([C:19]([C:22]([C:25]([F:28])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.CN1CCOCC1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][C:48](Cl)=[O:49])[CH:41]=1>C(Cl)Cl>[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][C:48]([NH:1][C@H:2]([C:6]([N:8]2[CH2:31][CH2:30][CH2:29][C@H:9]2[C:10]([NH:12][CH:13]([CH:14]([CH3:15])[CH3:16])[C:17](=[O:18])[C:19]([F:20])([F:21])[C:22]([F:23])([F:24])[C:25]([F:28])([F:26])[F:27])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5])=[O:49])[CH:41]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: O=C(Cl)CCc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Dissolve H-Val-Pro-Val-CF2CF2CF3.hydrochloride (185 mg, 0.37 mmol) in methylene chloride (10 mL) and cool to -20° C. while stirring. Add N-methylmorpholine (0.2 mL, 2.0 mmol) and immediately follow with a dropwise addition of 3-(3-pyridyl)propanoyl chloride in methylene chloride (5 mL) at such a rate as to maintain the internal reaction temperature at -10° C. or less. After completion of the addition, allow the reaction mixture to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 mL) and wash with 1N HCl (2×20 mL), saturated NaHCO3 (2×20 mL) and brine (1×20 mL). Dry (MgSO4) and concentrate in vacuo to give the title product in crude form. Immediately purify the crude product by flash chromatograpy (2×15 cm column eluted with 1:27 MeOH--CH2Cl2) to give the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[C@H:18]1[C:30]([OH:32])=[O:31].[C:34]([C@@H:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:38]=1)#[N:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[C@H:18]1[C:30]([O:32][C@H:36]([C:34]#[N:35])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:38]=1)=[O:31]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OC1CCCC1
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
2.96 g of dicyclohexylcarbodiimide were added at 0° C. to a stirred mixture of 3.6 g of the product of Step B, 30 ml of methylene chloride and 30 mg of 4-dimethylaminopyridine followed by the addition of a solution of 3.3 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 10 ml of methylene chloride. The mixture was stirred at 0° C. for 5 minutes and at 20°-25° C. for 3 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a cyclohexane-ethyl acetate mixture yielded 4.5 g of (S)α-cyano-3-phenoxybenzyl(1R,cis)2,2-dimethyl-3-[2-(cyclopentyloxycarbonyl)ethynyl]-cyclopropane-carboxylate with a melting point of =72° C.
Reaction SMILES: C(O[C:6](=[O:32])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:31])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[C:22]=1[OH:23])=[O:12])(C)(C)C.[F:33][C:34]([F:39])([F:38])C(O)=O.C(N(CC)CC)C.FC(F)(F)C(OCC)=O>C(Cl)Cl.C1COCC1>[F:33][C:34]([F:39])([F:38])[C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:31])[N:18]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=[CH:20][C:21]=2[C:22]=1[OH:23])=[O:12])=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCNC(=O)C(F)(F)F)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (30 mg, 0.068 mmol) was dissolved in CH2Cl2 (1.5 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (3 mL), triethylamine (0.050 mL, 0.34 mmol), and ethyl trifluoroacetate (2 mL), and the mixture was refluxed for 48 h. After cooling to r.t., the mixture was concentrated to dryness. The residue was partitioned between EtOAc and water, and pH was adjusted to about 4 with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 12 mg of the title compound as a pale yellow solid. MS: (+) m/z 435.31 (M+1).
Reaction SMILES: [CH3:1][C@:2]([NH:24]C(=O)OC(C)(C)C)([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:12][CH:13]=1)=[O:6])[CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C@:2]([CH3:1])([CH2:3][CH3:4])[NH2:24])=[CH:13][CH:12]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-1-methyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 98, 65 mg) in dry dichloromethane (3 mL) cooled to 0° C., TFA (0.700 mL, 9.08 mmol) was added dropwise. The reaction was stirred at that temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 (20 mL) added at 0° C., and extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a white solid (44 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25].N.C(Cl)Cl>CC#N.CO>[NH2:25][CH2:24][CH2:23][NH:26][C:2]1[N:7]2[N:8]=[C:9]([CH3:21])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1
Reactant: COc1ccc(-c2c(C)nn3c(Cl)cc(C)nc23)c(OC)c1
Reactant: NCCN
Agent: N
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2c(C)nn3c(NCCN)cc(C)nc23)c(OC)c1
Temperature: 25 °C

Procedure:
Dissolve 7-chloro-2,5-dimethyl-3-(2,4-dimethoxyphenyl)-pyrazolo[1,5-a] pyrimidine in 25 mL CH3CN, then add excess ethylenediamine (5 mL) and heat to 80° C. for 3-6 h under N2 with attached reflux condenser. (TLC: [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent). Cool to ambient temperature and evaporate to yellow oil. Partition between CH2Cl2 (50 mL) and 1.0 N NaOH (50 mL), and extract aqueous layer 2×30 mL CH2Cl2. Pool organic layers, dry over Na2SO4, filter and evaporate to yellow-white foam. Use without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:12]N1C(=O)N(O)C(=O)N(O)[C:14]1=[O:23].[O:24]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:23])=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)O)cc1
Product: CC(C)(C)c1ccc(C=O)cc1

Procedure:
A mixture of 0.445 g of 4-t-butyltoluene, 0.016 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (3% by mole relative to 4-t-butyltoluene), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 2 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-t-butylbenzoic acid and 4-t-butylbenzaldehyde in 97% and 1% yields, respectively, at 100% conversion of 4-t-butyltoluene.
Reaction SMILES: [CH:1]([NH2:3])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:5].Br[CH2:19][C:20](=O)[CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[S:5]1[CH:19]=[C:20]([CH2:21][CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[N:3]=[CH:1]1
Reactant: NC=O
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1cscn1
Yield: 39.7 %

Procedure:
Reflux formamide (2 mL, 50 mmol) and P2S5 (4.4 g, 10 mmol) dioxane (50 mL) for 2 hours. Add this crude solution to 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione (2.3 g, 7.7 mmol) in dioxane (100 mL) and reflux the resulting reaction solution for 1.5 hours. Add ethyl acetate (100 mL) and 1N sodium hydroxide (100 mL) to the mixture. Separate the organic phase, wash with brine (50 mL), dry (Na2SO4), filter and concentrate in vacuo to an oil. Perform chromatography (silica gel, 7:3 hexane/ethyl acetate) to afford 2-(2-thiazol-4-ylethyl)isoindole-1,3-dione (790 mg). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.80-7.88 (m, 2H), 7.69-7.75 (m, 2H), 7.08 (s, 1H), 4.10 (t, J=7 Hz, 2H), 3.28 (t, J=7 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23].ClC1N=C(NCCNC(=O)OC(C)(C)C)C(C#CC(OCC)OCC)=CN=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]([C:27]#[C:26][CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Agent: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NC(C)(C)CNC(=O)OC(C)(C)C)OCC

Procedure:
tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate is synthesized by treating tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4 yl]amino]ethyl]carbamate LCMS (ESI) (M+H) 427.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1nccc2ccncc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ccncc12
Temperature: 130 °C
Yield: 68 %

Procedure:
A pressure bottle, equipped with a magnetic stirrer, was charged with 1-hydroxy-2,7-naphthyridine (2.6 g, 17.8 mmol) and 100 mL of phosphorous oxychloride. The bottle was sealed and heated at 130° C. overnight. Upon cooling, the bottle was opened and the excess POCl3 was removed by evaporation in vacuo. The residue was treated with excess saturated Na2CO3 and extracted twice with CHCl3. The organic layer was washed with brine and dried (Na2SO4). Evaporation of the solvent afforded the product as a light brown solid (2.0 g, 68%, purity 90-95% based on NMR). The product was of suitable purity for use in the next step.