Azzindani/Open_Reaction_Data huggingface dataset:
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.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CC(N(C)C)=O>[N:64]1([C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:23]=[CH:24][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:10][CH:11]=3)[CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1
Reactant: C1COCCN1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)N4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy} pyridine-2-carboxylic acid (Example 20, 0.15 g, 0.38 mmol) in dry DMA (3 mL) was added HATU (0.14 g, 0.38 mmol) and DIEA (0.15 g, 1.13 mmol). The solution was stirred at rt for 0.5 h, followed by addition of morpholine (0.16 g, 1.88 mmol). The resulting solution was stirred at rt overnight, followed by prep-HPLC separation to give 77 mg (35%) pure product. 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 8.40 (s, 1H), 7.85 (m, 2H), 7.74 (m, 2H), 7.60 (m, 3H), 7.21 (m, 2H), 7.00 (m, 2H), 6.59 (s, 1H), 3.49 (m, 8H); MS ES 469 (M+H)+, calcd 469.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:34])([CH3:33])[C:13]32[CH2:36][CH2:35]3)[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:33])([CH3:34])[C:13]32[CH2:35][CH2:36]3)[N:12]=1
Reactant: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(NC(=O)OC(C)(C)C)=N2)C2(CC2)C(C)(C)O3)cn1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(N)=N2)C2(CC2)C(C)(C)O3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl[(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (13.75 g, 26.98 mmol) in chloroform (140 ml) was added trifluoroacetic acid (68 ml) in an ice-water bath, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (pre-column: NH-silica gel; main column: neutral silica gel, chloroform/methanol=100:0-10:1). To the purified product was added saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (pre-column: basic silica gel; main column: neutral silica gel, chloroform/methanol=100:0-10:1). The purified product was triturated with a mixture of hexane/ethyl acetate (4:1) (300 mL), and the mixture was stirred at 60° C. for 1 hour and room temperature for 4 days. The precipitate was collected, washed with mixture of hexane/ethyl acetate (4:1) (200 mL), and dried in vacuo at 50° C. to afford N-[(4′R)-2″-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl]-5-me thoxypyrazine-2-carboxamide (8.38 g) as a crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:7]([NH:9][C@H:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])([O-:3])=[O:2].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:7]([NH:9][C@H:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([O:14][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:13])=[O:8])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)ON1C(=O)CCC1=O
Temperature: 2.5 °C

Procedure:
12 g of (S)-3-(3,5-dinitrobenzamido)-3-phenylpropionic acid from reaction b) were dissolved in 120 ml of tetrahydrofuran and admixed with 3.92 g of N-hydroxysuccinimide. With cooling in an icebath at 0-5° C., 7.1 g of dicyclohexylcarbodiimide was added in portions to the reaction mixture. On completion of addition, the mixture was left in the icebath with further stirring until the solution reached room temperature. After the reaction ended (HPLC monitoring >95 area % conversion), the precipitated dicyclohexylurea was filtered off and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue digested at reflux in 250 ml of 2-propanol for 2 h. The product was filtered off with suction, washed with 2-propanol and dried at 50° C. under reduced pressure. The yield was 13.87 g; HPLC purity 98.8 area %.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][CH2:16][CH:11]([C:12](OC)=O)[CH2:10]2)=[CH:6][CH:5]=1.[OH-:21].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][CH2:16][C:11](=[CH2:12])[C:10]2=[O:21])=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1CCCN(Cc2ccc(OC)cc2)C1=O
Yield: 71.4 %

Procedure:
A solution of methyl N-(p-methoxybenzyl)nipecotate hydrochloride (30.7 g) and 8.4 g of sodium hydroxide in 900 ml of methanol and 45 ml of water is stirred at room temperature for seventeen hours. The solution is evaporated to dryness in vacuo, the residue diluted with toluene, and this again evaporated to dryness in vacuo. To the residue is added 1 liter of acetic anhydride and 140 ml of triethylamine, and the resulting mixture is heated under reflux for four hours. The reaction mixture is evaporated to dryness in vacuo, the residue taken up in chloroform, washed with water, dried, and concentrated in vacuo. The residual oil is chromatographed on silica gel using 1:1 hexane-ethyl acetate as the eluant, and yields 16.9 g of 1-(p-methoxybenzyl)-3-methylene-2-piperidone as a chromatographically pure yellow oil. Alternatively, the oil can be distilled to give analytically pure 1-(p-methoxybenzyl)-3-methylene-2-piperidone, b.p. 145°-155°/0.05 mm.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:45])[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21](Cl)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:43])[C@@H:14]1[OH:44])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46]([NH:53][C@@H:54]1[CH2:58][CH2:57][NH:56][CH2:55]1)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].[I-].[Na+]>C(#N)C>[C:49]([O:48][C:46](=[O:47])[NH:53][C@@H:54]1[CH2:58][CH2:57][N:56]([C:21]2[N:20]=[C:19]3[C:24]([N:25]=[CH:26][N:18]3[C@@H:16]3[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C@H:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:45])[C@@H:14]([OH:44])[C@H:15]3[OH:43])=[C:23]([NH:27][CH2:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:22]=2)[CH2:55]1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A suspension of (R)-2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (1 equivalent) and (3R)-(+)-3-(Boc-amino)pyrrolidine (4 equivalents) in acetonitrile is treated with a catalytic amount of sodium iodide and then heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 160° C. After 1 hour, the solvent is removed in vacuo; purification by column chromatography/crystallisation affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][NH:12][C:11](=[O:18])[CH:10]=2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[F:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:22])[C:11](=[O:18])[CH:10]=1
Reactant: O=c1cc(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To the yellow solution of 4-(4-bromo-2-fluorophenylamino)-5-nitropyridin-2(1H)-one (1.235 g, 3.78 mmol) dissolved in dry DMF (15 mL) at −5->0° C., was added NaH (182 mg, 4.55 mmol) (60% in oil). The color of solution turned into dark brown in 20 min at 0° C. The stirring was continued at r.t. for 40 minutes, followed by the addition of MeI (283 uL, 4.54 mmol) through a syringe at 5° C. The resulted solution was stirred at r.t. for 36 hours. The desired compound started to precipitate out of solution after 20 min of MeI addition. Water was added, and the precipitate was vacuum filtered, washed with water, and dried at 40° C. under a high vacuum for 2.5 hours. The product was used for the next reaction without further purification. (1.12 gram, 87% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:37]=3[N:36]([CH3:38])[CH:35]=[C:34]4[CH:39]=O)[N:25]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22].[OH-].[Na+]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:37]=3[N:36]([CH3:38])[CH:35]=[C:34]4[CH2:39][N:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]3)[N:25]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Ethyl 4-piperidinecarboxylate hydrochloride (969 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (396 mg) was added to a solution of NaOH (200 mg) in ethanol (10 mL). After stirring for 0.5 hour, ethanol was evaporated off and then dichloromethane (40 mL) containing AcOH (0.5 mL) was added to the residue. NaBH(OAc)3 (1.06 g) was added to the above mixture. The reaction mixture was stirred at room temperature overnight and then terminated by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D79) (308 mg) as a yellow solid. MS (ES): C29H33ClN4O4 requires 536; found 537.3 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.CCO.[OH-].[Na+]>CO>[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)=[O:16]
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(C=Cc1cccc(Cl)c1Cl)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4′-Tetrahydropyranyloxy-acetophenone (1.98 g, 9.0 mmol),ii 2,3-dichlorobenzaldehyde (1.93 g, 11.0 mmol), EtOH (15 mL), and MeOH (15 mL) were combined in a 100 mL round bottom flask with a stir bar. After all of the reactants were dissolved, 50% (w/v) aq. NaOH (1.0 mL, 19 mmol) was added. The flask was stoppered and stirred at room temperature for 8 h. The resulting white precipitate was filtered, washed with EtOH (1 mL, 3×), and allowed to air dry to afford 2.95 g of THP-4Al as a white powder (87% yield). The product was used without further purification. TLC: Rf=0.40 (hexane/EtOAc 4:1); Melting point: 116-118° C.; 1H NMR: (300 MHz, Acetone-d6) δ 8.15, 7.18 (AA′XX′ peak, Jaa′=Jxx′=2.5, Jax=8.4, Jax′=0.4 Hz, 2H), 8.13 (d, J=16 Hz, 1H), 8.04 (dd, J=7.9, 1.4 Hz, 1H), 7.89 (d, J=16 Hz, 1H), 7.64 (dd, J=7.9, 1.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 5.61 (t, J=3.0 Hz, 1H), 3.82 (ddd, J=11.5, 8.4, 2.6 Hz, 1H), 3.61 (dtd, J=11.5, 4.0, 1.3 Hz, 1H), 1.86 (m, 3H), 1.66 (m, 3H); 13C NMR: (75 MHz, DMSO-d6) δ 187.23, 161.54, 138.27, 136.06, 133.45, 132.73, 131.77, 131.48, 130.95, 128.36, 126.93, 126.31, 116.38, 96.22, 61.89, 30.14, 25.13, 18,67; IR (ATR): 2964, 1656, 1608, 1595, 1573, 1556, 1507, 1455, 1425, 1411, 1372, 1326, 1314, 1248, 1222, 1205, 1173, 1155, 1121, 1106, 1035, 1020, 961 cm−1; ESI-MS: expected, 376.1; observed, m/z 376.9 [M+H+].
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[N:20]=2)[CH:7]=1)=[O:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][C:30]=1[CH3:37]>C1COCC1>[Br:25][C:21]1[N:20]=[C:19]([CH2:18][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[C:30]([CH3:37])[CH:31]=3)=[CH:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc([Mg]Br)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3nc(C)ccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 85 mg (0.204 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide and 0.896 mL 0.448 mL, 0.5 M in THF) of 4-methoxy-3-methylphenylmagnesium bromide in 1 mL of THF. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to afford 27.9 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one as a white solid. LC-MSD, m/z for C24H20BrN3O3 [M+H]: 478.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.6 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1.O>C(O)CCC>[CH3:28][N:26]1[CH:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)=[N:19][N:18]=3)[N:15]=2)[CH:24]=[N:25]1
Reactant: NNC(=O)Cc1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCCCO
Solvent: O
Product: Cn1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 120 °C
Yield: 65 %

Procedure:
Quinolin-6-yl-acetic acid hydrazide (188 mg, 0.93 mmol) and 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (202 mg, 0.93 mmol, Example 1: step a) were dissolved in butanol (120 mL). The reaction mixture was heated to 120° C. overnight fitted with water cooled refluxing condenser and argon line. The reaction was concentrated in vacuo followed by HPLC purification (5-65% CH3CN over 40 min) resulting in the title compound as a tan solid (201.6 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH:19](=[N+:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:19]([N:26]([CH3:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1Cl
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(-c2ccc(F)c(Cl)c2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(3-chloro-4-fluorophenyl)-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:27])[C:5]([N:7]([CH3:26])[CH:8]1[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][N:10]2[C:16](=[O:25])[C:17]([OH:24])=[C:18]([C:20]([O:22]C)=O)[N:19]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CO>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:20]([C:18]2[N:19]=[C:9]3[CH:8]([N:7]([CH3:26])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:27])[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][N:10]3[C:16](=[O:25])[C:17]=2[OH:24])=[O:22])=[CH:38][CH:37]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C)CC2N(C)C(=O)C(=O)N(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-3-hydroxy-8-methyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate prepared as described in Step 2 was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluorobenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound (trifluoroacetic salt) as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 10.01 (bs, 1H), 7.63 (dd, J=8.6 Hz, J=5.7 Hz, 2H), 7.29 (t, J=8.6 Hz, 2H), 5.53-5.30 (m, 2H), 4.82-4.68 (m, 2H), 4.25-4.13 (m, 3H), 3.95 (bs, 1H), 3.48-3.42 (m, 1H), 3.25 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 3.13 (s, 3H); MS (ES) C22H27FN6O5 requires 474. Found: 475 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.[Li].C([Li])CCC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[N:19][CH:20]=1.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]([CH:22]=[O:23])[C:18]([F:21])=[N:19][CH:20]=1
Reactant: O=CN1CCCCC1
Reactant: Fc1ccc(Br)cn1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cnc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
A solution of lithium di-iso-propylamine (5 mL, 35 mmol) in anhydrous THF (40 mL) was cooled to −78° C. under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30 mmol) was added. The mixture was then stirred at −78° C. for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at −78° C. for 90 min. N-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspension at −78° C. and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10% (w/v) aqueous solution of citric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude product from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52% yield) as pale beige flaky crystals. 1H-NMR (500 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.70 (dd, 1H), 8.55 (dd, 1H). MS: m/z 236, 238 [MNa+], 204, 206 [MH+], 176, 178 [MH-CO+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 87.7 %

Procedure:
To a biphasic solution of 4-amino-1-benzylpiperidine (6.0 g, 31.6 mmol), K2CO3 (8.71 g, 63.1 mmol) in CH2Cl2 (200 mL) and water (100 mL) was added benzoyl chloride (4.86 g, 34.7 mmol) in 20 mL of CH2Cl2 at 0° C. with stirring. After stirring for 4 h at room temperature, the layers were separated. The organic layer was washed with water, dried over MgSO4 and filtered. The solvent was removed in vacuo to obtain 1-benzyl-4-benzamidopiperidine (8.16 g, 87% yield) as a white solid. It was used in the next step without purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([C:15]1[S:14][C:13]([CH3:12])=[CH:17][CH:16]=1)=[O:11]
Reactant: Cc1cccs1
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(C)s1
Temperature: 0 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a suspension of aluminum trichloride (2.75 g, 20.6 mmol) and methyl 2-chloro-2-oxoacetate (1.90 mL, 20.7 mmol) in dry DCM (25 mL), cooled at 0° C. and under nitrogen atmosphere, is added 2-methylthiophene (1.00 mL, 10.33 mmol) dropwise. The reaction is stirred at RT for 15 hours. Then the mixture is cooled at 0° C. ice-water is slowly added and the organic phase is washed with aq. NaHCO3 and brine, dried over Na2SO4 and evaporated to obtain intermediate I266 as a brown oil (1.9 g, quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[CH:35]([CH3:39])[C:36]([NH2:38])=[O:37]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C@@H:35]([CH3:39])[C:36]([NH2:38])=[O:37])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: CC(Br)C(N)=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN([C@@H](C)C(N)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and 2-bromopropionamide were reacted to give the racemic mixture. The enantiomers were separated by SFC to give 560. LCMS m/z: 259.7 (2M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Reactant: ClCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1F
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-3-nitrophenol (2.1 g, 13 mmol), potassium carbonate (2.2 g, 16 mmol), 2-(chloromethyl)benzo[d]thiazole (2.4 g, 13 mmol) and DMF (15 mL) was stirred at 80° C. for 6 h. The reaction mixture was cooled to RT and poured onto ice water (300 mL). Solid precipitate was collected by vacuum filtration and dried in a vacuum oven at 60° C. to provide the title product, which was used without purification. MS (ESI): mass calcd. for C14H9FN2O3S, 304.1; m/z found, 305.1 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ 8.15 (t, J=6.7, 1H), 8.08-8.01 (m, 1H), 7.90-7.84 (m, 1H), 7.63-7.53 (m, 3H), 7.52-7.45 (m, 1H), 5.75 (s, 2H).