Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.Cl.[NH2:31][OH:32]>C(O)(=O)C.O.N1C=CC=CC=1.C(O)C>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[CH:3]=[N:31][OH:32])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: NO
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(C=NO)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (23.0 g, 0.053 mole) in acetic acid is treated with 54 ml of 2.5N H2 SO4 and stirred at 70° C. for 12 hours. A 15 ml portion of the reaction solution is diluted to a total volume of 100 ml with water, the resulting precipitate is separated, washed with water, treated with a solution of hydroxylamine hydrochloride (1.0 g, 0.014 mole) in pyridine and ethanol, heated at 85° C. for several hours, cooled and concentrated in vacuo to give a solid residue. Recrystallization from aqueous ethanol, ethanol and toluene gives the title compound mp 148°-151° C., identified by elemental and NMR analyses.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:6]4[CH:5]=[C:4]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:24][CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:34][CH2:33]1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc(Oc3ccc(Nc4cc(-c5ccccc5)nc(N)n4)cc3)ccn2)CC1

Procedure:
This material is prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy} pyridine-2-carboxylic acid (Example 20) and 1-methylpiperizine. 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 10.19 (s, 1H), 8.42 (d, 1H), 7.90 (m, 2H), 7.74 (m, 3H), 7.59 (m, 4H), 7.22 (m, 3H), 7.06 (m, 2H), 6.60 (s, 1H), 4.51 (m, 1H), 4.08 (m, 1H), 3.45 (m, 3H), 3.17 (m, 3H), 2.78 (s, 3H); MS ES 482 (M+H)+, calcd 482, RT=1.86 min.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[O:24][C:25]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])=[CH:26][N:27]=3)[CH2:10]2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>CO.C1COCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[O:24][C:25]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])=[CH:26][N:27]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(-c2cnc(N[C@@H]3CCCC[C@H]3N[C@H]3CCCN(c4ccc(C(F)(F)F)cc4)C3)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2cnc(N[C@@H]3CCCC[C@H]3N[C@H]3CCCN(c4ccc(C(F)(F)F)cc4)C3)o2)c1
Yield: 71 %

Procedure:
Methyl 3-(2-(((1R,2R)-2-(((S)-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)cyclohexyl)amino)oxazol-5-yl)benzoate (470 mg, 0.866 mmol) was dissolved in a mixed solvent of MeOH (3.5 mL) and THF (3.5 mL), then 2 M of aqueous LiOH (7 mL, 14 mmol) was added. The resultant mixture was stirred at rt for 16 h. LC/MS check showed the reaction was completed. The reaction was cooled in an ice-bath, 3 M HCl was added dropwise to adjust pH ˜3. The reaction mixture was concentrated. The resulting residue was purified using prep HPLC (Phenomenex Luna Axia, 5μ, 30×100 mm, 40-80% B, gradient over 10 min, hold at 80% B for 2 min). The desired fractions were concentraed to almost dryness, and the residue was lyophilized in CH3CN—H2O to afford the title compound (2 TFA salt) as a beign colored powder (465 mg, 0.615 mmol, 71.0% yield). Anal. Calcd. for C28H31F3N4O3 m/z 528.2, found: 529.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:33]1[C:42]2[C:37](=[CH:38][C:39]([C:43]([OH:45])=O)=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C.[ClH:55].Cl.[NH2:57][CH:58]1[CH:63]2[CH2:64][CH2:65][N:60]([CH2:61][CH2:62]2)[CH2:59]1>CN(C=O)C>[ClH:55].[N:60]12[CH2:65][CH2:64][CH:63]([CH2:62][CH2:61]1)[CH:58]([NH:57][C:43]([C:39]1[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=1)[N:33]=[CH:34][CH:35]=[CH:36]3)=[O:45])[CH2:59]2
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CN2CCC1CC2)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
Firstly, 319 mg (0.99 mmol) of TBTU and 137 mg (1.01 mmol) of HOBt are added to a solution of 182 mg (1.05 mmol) of quinoline-6-carboxylic acid and diiso-propylethylamine (620 mg, 4.8 mmol) in 4 mL of DMF at RT, and then 200 mg (1.0 mmol) of 3-aminoquinuclidine dihydrochloride are added. The mixture is stirred at RT for 4 h. For a workup, it is concentrated and taken up in a mixture of chloroform and excess aqueous NaOH. The phases are separated and the aqueous phase is back-extracted several times with chloroform. The combined organic phases are dried over sodium sulfate and concentrated, and the crude product is chromatographed on a silica gel column (mobile, chloroform:methanol: conc. NH3=100:20:4). The resulting product is taken up in THF, excess HCl in diethyl ether is added, and the mixture is concentrated and dried under high vacuum. 136 mg (47% yield) of the hydrochloride are obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([C:14]([NH:16][C@@H:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:11]=[C:10]([Cl:29])[C:5]=1[C:6]([O:8]C)=[O:7].CO>O.O1CCCC1>[Cl:3][C:4]1[CH:13]=[C:12]([C:14]([NH:16][C@@H:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:11]=[C:10]([Cl:29])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of sodium hydroxide (0.62 g, 15.5 mmol) in water (100 mL) was added to a solution of 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (5.62 g, 14.0 mmol) in tetrahydrofuran (100 mL). The solution was stirred overnight at room temperature. Tlc indicated that the reaction was not complete. 1 M NaOH (20 mL) was added and the mixture was heated at reflux for 6 h. Methanol (100 mL) was added and the mixture was stirred overnight at room temperature. Again, tlc indicated that the reaction was not complete so the reaction mixture was heated at reflux for 2 h, 1 M NaOH (100 mL) was added and the solution was heated at reflux for a further 4 h. The reaction mixture was allowed to stand overnight at room temperature, then the solvent was evaporated, and water (100 mL) and 1 M HCl (200 mL) were added. The mixture was stirred for 20 min and then the white solid was filtered off and dried overnight in a vacuum oven (25 mm Hg, 60° C.) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid (4.84 g, 89%) as a white solid, mp 213-215° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:33]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH:33]1([C:36]([NH:38][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4([C:22]([NH:24][C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:23])[CH2:21][CH2:20]4)=[O:18])=[C:11]([F:32])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)C1CC1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.25 g, 0.541 mmol) (as prepared in Example 1), cyclopropanecarboxamide (0.092 g, 1.083 mmol), xantphos (0.014 g, 0.024 mmol), and cesium carbonate (0.265 g, 0.812 mmol) were dissolved in dry dioxane (5.41 mL) and argon was bubbled through the mixture for 5 minutes. Pd2(dba)3 (7.44 mg, 0.00812 mmol) was added and additional argon was bubbled through the system. It was then fitted with a reflux condenser and a balloon of argon and heated at 100° C. for 20 hours. The reaction mixture was cooled to room temperature and then partitioned between water (40 mL) and ethyl acetate (70 mL). The layers were separated and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, and evaporated to yield a peach-colored solid. It was stirred in dichloromethane (10 mL) and a cream-colored solid was collected by suction filtration and washed with additional dichloromethane to yield N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.238 g, 86% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.89 (s, 1H), 9.79 (s, 1H), 8.20 (d, 1H), 8.07 (dd, 1H), 7.63 (d, 1H), 7.56 (m, 3H), 7.16 (m, 2H), 6.74 (dd, 1H), 1.95 (quintet, 1H), 1.62 (m, 2H), 1.56 (m, 2H), 0.75 (m, 4H); MS (ESI) m/z: 511.1 (m+H+).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][C:4](=O)[OH:5].C(Cl)(=O)C(Cl)=O.C([SnH](CCCC)CCCC)CCC>CN(C=O)C>[CH2:10]([O:9][C:7](=[O:8])[CH:2]([NH:1][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:3][CH:4]=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Z-Asp-OBn (10 g, 0.028 mol) in MC (200 ml), oxalyl chloride (2.93 ml, 0.0336 mol) and a catalytic amount of DMF were added at 0° C. and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was dissolved in benzene (400 ml), and tributyltin hydride (15.1 ml, 0.056 mol) and a catalytic amount of Pd(0) were added slowly at 0° C. and stirred at room temperature overnight. After the solvent was evaporated, ether (100 ml)/10% KF in water (100 ml) was added and stirred at room temperature for 2 hrs, followed by filtration to give a biphasic solution. The organic layer was separated and concentrated to give a crude product, which was purified by column chromatography to obtain the title compound, Z-Asp-OBn aldehyde (6 g) as pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:27])[CH3:28])=[CH:18][CH:17]=2)[OH:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN(C(C)C)C(C)C)cc2)cc1
Solvent: CO
Product: COc1ccc(-c2oc3cc(OC)ccc3c2C(O)c2ccc(OCCN(C(C)C)C(C)C)cc2)cc1
Yield: 54.9 %

Procedure:
1.5 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzofuran-3-yl][4-[2-diisopropylaminoethoxy]phenyl]methanone was reduced to the carbinol by the method described in Example 1. This yielded 830 mg of the title compound as an oily solid.
Reaction SMILES: [O:1]1[C@H]2[C@@H]1C(=O)[C@H]1[C@@H]2[C@@H]1C(OCC)=O.[F:14][C:15]1[C:16](=[O:26])[C@H:17]2[C@@H:19]([CH:20]=1)[C@@H:18]2[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[F:14][C:15]1[C:16](=[O:26])[C@H:17]2[C@@H:19]([CH:20]=1)[C@@H:18]2[C:21]([O:23][CH2:24][CH2:25][OH:1])=[O:22]
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C(F)C(=O)[C@@H]21
Reactant: CCOC(=O)[C@@H]1[C@H]2C(=O)[C@@H]3O[C@@H]3[C@@H]12
Product: O=C(OCCO)[C@H]1[C@@H]2C=C(F)C(=O)[C@@H]21
Yield: 152.1 %

Procedure:
In addition, in the same manner as described above, from 5.45 g of ethyl (1S, 3R, 4R, 5R, 6S)-3,4-epoxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate, 1.01 g of ethyl (1S, 5R, 6S)-3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxyl ate, and 1.67 g of 2-hydroxyethyl (1S, 5R, 6S)-3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate were obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH:12]([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.IC>C1COCC1.O>[Br:1][C:2]1[C:10]2[C:6](=[C:7]([CH3:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Solvent: CCc1ccccc1
Product: Cc1c2cccc(Br)c2nn1C
Temperature: 2.5 °C

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (5.49 g, 26.0 mmol) in 100 mL of THF at −78° C. was added a 2.0 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (19.5 mL, 39.0 mmol). The resulting dark orange solution was stirred at 0-5° C. for 15 m, then rechilled at −78° C. for 15 m. Iodomethane (2.5 mL, 40 mmol) was added, and the orange solution allowed to slowly warm to RT over 17 h period with stirring. Water (100 mL) was added, and the mixture was extracted with 100 mL of ether. The organic layer was washed with 200 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to an orange solid. Column chromatography (0→50% EtOAc/hexanes) afforded 7-bromo-2,3-dimethyl-2H-indazole (8: R=R″=Me; 5.28 g, 90%) of as a yellow-stained white solid that was used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11]([NH:33][CH2:32][CH2:31][NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[C:12]=3[O:14][CH3:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNc1c(F)c(F)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNc1c(F)c(NCCNc2ccccn2)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-methylamino-4-oxoquinoline-3-carboxylic acid (500 mg, 1.54 mmol), N-2-pyridyl-1,2-ethanediamine (423 mg, 3.03 mmol) and triethylamine (0.430 mL, 3.09 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (hexane: EtOAc 1:1→EtOAc) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methylamino-7-[2-(2-pyridylamino)ethylamino]-4-oxoquinoline-3-carboxylic acid (373 mg, 55%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8](O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1cccc2c1OC(C)(C)C2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(C)(C)C2N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (29 ml) is added to a stirred solution of the product obtained in Step 4. (25.4 g) in methylene chloride (560 ml) at RT under nitrogen. Methanesulfonyl chloride (11.1 ml) is added dropwise to the mixture which is cooled to 0° C. The mixture is stirred for 3 hours at RT, cooled to 0° C., piperidine (128 ml) added and stirring continued at RT overnight. Sat'd aq. sodium bicarbonate is added to the mixture, the phases separated and the organic phase washed with sodium bicarbonate, sat'd NACl, dried, filtered and evaporated in vacuo. The residue is dissolved in toluene and evaporated in vacuo affording the desired product as the hydrochloride salt.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O1CCCC1>O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)#[N:15]
Reactant: COC=C1CCC(c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1

Procedure:
A mixture of 14.25 g of p-[4-(methoxymethylene)cyclohexyl]benzonitrile (purity 96.1%) and 200 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 30 minutes. The reaction mixture was subsequently poured into 300 ml of water and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed with 200 ml of water, dried over magnesium sulphate and concentrated. There were thus obtained 13.75 g (103%) of crude product of 4-(p-cyanophenyl)cyclohexanecarboxaldehyde (trans/cis ratio about 3:1) as a colourless, slowly crystallizing oil. Recrystallization of this material from 1.3 l of hexane gave 3.71 g (29%) of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde (purity 99.5%) as long, colourless needles of m.p. 57.1° C. The mother liquor was concentrated to a volume of 1 l and again set aside for crystallization, there being obtained as the second crystallizate 1.20 g of colourless needles containing 97% of trans-aldehyde and 3 % of cis-aldehyde. The separated mother liquor was now concentrated, the residue was again heated to reflux for 30 minutes in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) and the mixture was then worked-up in the same manner as on the first occasion. The crude product obtained was combined with the second crystallizate (1.2 g) and recrystallized from 900 ml of hexane, whereby 3.56 g (28%) of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde (purity 99.7%) could again be isolated as long, colourless needles. The mother liquor (containing 4.2 g of crude product) was no longer worked-up. Total yield after two cycles: 7.27 g (57%) of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde; m.p. 57.1° C.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:21]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[S:24][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Yield: 90 %

Procedure:
The title compound was prepared from 4-anisoyl chloride and 2-(4-methoxyphenyl)benzo[b]thiophene (Part A) as a tan solid in 90% yield following recrystallization from THF-hexanes.
Reaction SMILES: C[O:2][C:3]1[C:4](=O)[CH:5]([C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[CH3:19][NH:20][NH2:21]>C(O)(=O)C.O>[CH3:19][N:20]1[C:4]2[C:3](=[O:2])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]=2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:21]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)CC2=O
Reaction time: 24 h
Yield: 67.5 %

Procedure:
A solution of ethyl (3-methoxy-5,5-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate (15.50 g, 0.061 mol) in acetic acid (100 mL) was treated dropwise with a solution of methyl hydrazine (3.49 mL, 0.066 mol) dissolved in acetic acid (50 mL). After 24 hours at room temperature, the reaction mixture was diluted with water (2 L) under vigorous stirring. The resulting precipitate was filtered and washed with water to obtain the title compound (10.30 g, 67.6% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:8])[CH:5]([OH:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:7][CH:5]([CH3:6])[CH:4]([CH3:8])[CH3:3])[N:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)C(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(C)Oc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.18 g of 3-methyl-2-butanol was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.35 g of 4-chloro-6-(1,2-dimethylpropyloxy)pyrimidine.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[C:19]3[C:28](=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:30][C:18]=3[C:17]=2[F:39])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[C:19]3[C:28](=[O:38])[NH:29][CH2:30][C:18]=3[C:17]=2[F:39])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (5.5 mg, 9.76 μmol) in DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction mixture was stirred at RT for 1 h, and concentrated in vacuo. The resulting crude material was reconstituted in DMF and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (55-80% gradient, 0.035% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×50 mL), dried over anhydrous Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The residue was recrystallized from THF/hexane to give a TFA salt of the title compound. [M+H] calc'd for C16H18FN5O2S, 364; found, 364.