Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CC[C@@H](O)[C@H]1C(O)=O)(OC(C)(C)C)=O.CC(C)([O-])C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30](OC)=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>CS(C)=O>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COc1ccc2c(Cl)nccc2c1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc2cnccc2c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 284.8 %

Procedure:
To a solution of N-BOC-3-(R)-hydroxy-L-proline (892 mg, 3.89 mmol) in DMSO (40 mL) at the ambient temperature was added potassium tert-butoxide (1.34 g, 12.0 mmol) in one portion. The formed suspension was stirred at this temperature for 30 min before being cooled to 10° C. 1-chloro-6-methoxy-isoquinoline (example 11, Step 2) (785 mg, 4.05 mmol) was added as solid in one portion and the final mixture was stirred at the ambient temperature for 12 h. Quenched with iced 5% citric acid (aq), extracted with EtOAC (100 mL). The aqueous phase was extracted with EtOAC again. The combined organic layers were washed with 5% citric acid (aq) and brine respectively, dried over MgSO4, filtered. The filtrate was evaporated in vacuo to dryness to yield 1.49 g (99%) of the desired product as an off-white foam. This material was used in the next step reaction as crude without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Li+].[OH-].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].C[CH2:21][O:22]CC>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:17]([C:13]3[O:12][CH:16]=[CH:15][CH:14]=3)[O:18][C:21]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1oc(-c2ccco2)nn1-c1ccc(Cl)cc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a suspension of 1-(4-chlorophenyl)hydrazine as the hydrochloride salt (89.5 mg, 0.5 mmol) in Et2O (4 mL) was added a 2 N solution of LiOH (1 mL), and the resulting mixture was stirred for 15 minutes. After the system became homogeneous, the organic layer was separated and dried over Na2SO4. The resulting ethereal solution of carbohydrazide as a free base was cooled to −5° C., and then a solution of furan-2-carbonyl chloride (65 mg, 0.5 mmol) in 5 mL of THF was added dropwise to the resulting mixture. After stirring at 0° C. for 30 minutes, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was then separated, washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (5-50% EtOAc in hexane) to provide 100 mg (0.382 mmol, yield 76.3%) of 3-(4-chloro-phenyl)-5-furan-2-yl-3H-[1,3,4]oxadiazol-2-one with an HPLC purity of 99.9%. LC-MS [M+H] 263.7 C12H7ClN2O3+H, expected 263.01). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH3:37][N:38]=[C:39]=[O:40]>>[NH2:36][C:15]1[N:16]=[C:17]([N:19]2[CH:28]([CH3:29])[CH2:27][C:26]3[C:21](=[CH:22][C:23]([CH:30]4[CH2:31][CH2:32][N:33]([C:39]([NH:38][CH3:37])=[O:40])[CH2:34][CH2:35]4)=[CH:24][CH:25]=3)[CH2:20]2)[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=1
Reactant: CN=C=O
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CNC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and methyl isocyanate. LCMS (M+H)+: m/z=479.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH:8]=[C:7]([CH3:11])[S:6]1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])=[O:4]
Reactant: COC(=O)C1SC(C)=CC1O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C)cc1O
Yield: 75 %

Procedure:
17.4 parts of 3-hydroxy-5-methyldihydrothiophene-2-carboxylic acid methyl ester are dissolved in 100 parts by volume of methylene chloride. 14.9 parts of sulfuryl chloride in 20 parts by volume of methylene chloride are added in the course of 30 minutes at 10° C., whilst passing nitrogen into the mixture. The mixture is then distilled. 12.9 parts (75% of theory) of 3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester of boiling point 67°-70° C./0.3 mbar are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:15]1=[O:23])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
2-Isopropylphenol was methylated and then formylated to give 3-isopropyl-4-methoxybenzaldehyde. 3-Isopropyl-4-methoxybenzaldehyde was condensed with 2-oxindole to give 0.3 g of 3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18]>>[Cl:11][C:12]1[C:13]([NH:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])=[N:14][CH:15]=[C:16]([C:17]#[N:18])[CH:19]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)CCNc1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of beta-alanine tert-butyl ester (5.88 g, 40.4 mmol), TEA (5.6 mL, 40.4 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 7.0 g, 40.4 mmol) was prepared and stirred at RT for 24 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. The residue taken up with EtOAc (100 mL) and washed with water (2×100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder (8.3 g, 72%). 1H NMR (DMSO-d6, 400 MHz) δ 8.44 (1H, d), 8.08 (1H, d), 7.52 (1H, t), 3.62 (2H, m), 2.50 (2H, m), 1.35 (9H, s).
Reaction SMILES: [Si](O[CH2:9][CH:10]=[N:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])(C(C)(C)C)(C)C.[F:18][C:19]1[CH:20]=[CH:21]C(C=O)=[N:23][CH:24]=1.CC([S@@](N)=O)(C)C>>[F:18][C:19]1[CH:20]=[CH:21][C:9]([CH:10]=[N:11][S@:12]([C:14]([CH3:15])([CH3:16])[CH3:17])=[O:13])=[N:23][CH:24]=1
Reactant: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Reactant: O=Cc1ccc(F)cn1
Agent: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)[S@](=O)N=Cc1ccc(F)cn1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 21, using 5-fluoropyridine-2-carbaldehyde and (S)-2-methylpropane-2-sulfinamide as the starting materials. 1H NMR (300 MHz, CDCl3) δ ppm 8.67 (s, 1H) 8.58 (s, 1H) 8.06 (dd, J=8.29, 4.52 Hz, 1H) 7.51 (t, J=7.91 Hz, 1H) 1.20-1.33 (m, 9H). The product was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]O.[BrH:18].[C:19]1([PH+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[Br-:18].[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][P+:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Br
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccccc1OCc1ccccc1Cl
Solvent: CC#N
Product: Clc1ccccc1COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 99.7 %

Procedure:
A solution of 3.775 g (15.18 mmol) of [2-(2-chlorobenzyloxy)phenyl]methanol from Example 78A in 60 ml of acetonitrile is mixed with 4.949 g (14.42 mmol) of triphenylphosphonium hydrobromide and heated to reflux for 3 hours. The reaction solution is then concentrated to dryness, and the resulting oil is taken up and triturated in diethyl ether. The product crystallizes as a white solid during this. After filtration, the solid is dried in a drying oven at 50° C. overnight. 8.247 g (91% yield) of crystalline product are obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:15])([F:17])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47]1)=[O:19]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 71.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (591 mg, 1.32 mmol, 72%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:6][CH:7]=1.Cl[Sn]Cl>CCO>[NH2:16][C:4]1[C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(c1cccnc1)c1ncc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)cnc1C(=O)c1cccnc1
Temperature: 80 °C

Procedure:
A mixture of the (5-Chloro-3-nitro-pyridin-2-yl)-pyridin-3-yl-methanone from Step 2 above (30 mg, 0.11 mmol) and SnCl2 (200 mg, 0.88 mmol) in EtOH (3 mL) was heated at 80° C. in an oil bath for 3 days. The progress of the reaction was followed by LCMS and upon completion the solvent was removed and treated with aqueous NaOH to adjust the pH to 10-11. This cloudy mixture was extracted with EtOAc and washed with water and brine. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the residue separated by preparative HPLC (20→80% gradient of ACN-water) and pure product fractions were treated with NaHCO3 and extracted with EtOAc to provide (3-amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone. MS m/z: 234.1 (M+H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1>C(OCC)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:13]([F:19])=[CH:14][C:15]([CH3:18])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(F)c1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S(=O)(=O)Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 2.91 g (25 mmol) of chlorosulfonic acid and then 1.3 g (5 mmol) of 4-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-3-fluorotoluene. The mixture was stirred at 80° C. for 3 hours and cooled to room temperature. The mixture was added onto ice in small portions, and 30 ml of ethyl acetate was added to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to vacuum distillation to distill off ethyl acetate, to obtain a title compound as 1.66 g of a crystal. Yield: 93%
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>>[CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]3[CH:25]=[C:24]([O:23][CH3:22])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=3)=[N:10][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(-c2nc(N)sc2CC2CCCCC2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)Nc2nc(-c3ccc(O)cc3)c(CC3CCCCC3)s2)cc(OC)c1OC
Yield: 60.1 %

Procedure:
A procedure similar to that in Example 4 was used. 5-cyclohexylmethyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 47 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1) to obtain a product as a white solid in a yield of 60.1%, mp: 193-194└. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜0.98 (2H, m), 1.05˜1.28 (3H, m), 1.58˜1.88 (6H, m), 2.75 (2H, d, J=7.28 Hz, CHCH2Ar), 3.74 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.97 (3H, s, OCH3), 6.77 (2H, d, J=8.44 Hz, ArH), 6.98 (2H, s, ArH), 7.29 (2H, d, J=8.44 Hz, ArH); EI-MS m/e (%): 496.1 (M+, 64), 413.1 (48), 195.1 (100); HREI-MS Calcd. for C27H32N2O5S: 496.2032. found: 496.2040. Anal. Calcd. for C27H32N2O5S: C, 65.30; H, 6.49; N, 5.64. found: C, 65.11; H, 6.55; N, 5.70.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:23])[C:11]3[C:16]([C:17]=2[N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:4][CH:3]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>CN(C=O)C.O>[C:24](=[O:25])([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:23])[C:11]3[C:16]([C:17]=2[N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:4][CH:3]=1)[O:27][C:5]([CH3:8])([CH3:6])[CH3:4]
Reactant: COc1ccc2c([N+](=O)[O-])c(-c3ccc(O)cc3)[nH]c(=O)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c([N+](=O)[O-])c(-c3ccc(OC(=O)OC(C)(C)C)cc3)[nH]c(=O)c2c1
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-7-methoxy-4-nitroisoquinolin-1(2H)-one (50.0 mg, 0.16 mmol, 1.0 eq.), K2CO3 (22.15 mg, 0.16 mmol, 1.0 eq.), and Boc2 (34.9 mg, 0.16 mmol, 1.0 eq.) in DMF (1 ml) degassed with argon in a sealed tube is stirred at a.t. for 18 hours. The reaction medium is diluted with H2O. The organic phases are extracted with ethyl acetate (twice), washed with a saturated solution of NaCl (twice), dried over MgSO4 then concentrated under reduced pressure, in order to obtain a pure product (yield=100%).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.N1CCCC1.CC(O[C:19]([NH:21][C@@H:22]([C:26]([OH:28])=O)[CH:23]1[CH2:25][CH2:24]1)=[O:20])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH2:45]([N:47]1[CH:51]=[C:50]([C:52]2[N:57]=[C:56]3[C:58](C(O)=O)=[CH:59][N:60](COCC[Si](C)(C)C)[C:55]3=[N:54][CH:53]=2)[CH:49]=[N:48]1)[CH3:46].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1>>[CH:23]1([C@@H:22]([NH:21][C:19]([C:58]2[C:56]3[C:55](=[N:54][CH:53]=[C:52]([C:50]4[CH:49]=[N:48][N:47]([CH2:45][CH3:46])[CH:51]=4)[N:57]=3)[NH:60][CH:59]=2)=[O:20])[C:26]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)=[O:28])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: FC1(F)CCNC1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: C1CCNC1
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(F)(F)C4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3,3-difluoropyrrolidine hydrochloride for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. MS: (M+H)+=444.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(Nc2cc(N3CCOCC3)ncn2)cc1
Temperature: 200 °C
Yield: 89 %

Procedure:
50 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 17 mg of morpholine and 64 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 30 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N-(4-Methoxyphenyl)-6-morpholinopyrimidin-4-amine in the form of a colorless solid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: C[C@H]1c2ccccc2-c2ccc(F)cc2N1C(=O)c1cccc(O)c1

Procedure:
The enantiomers of 3-[(3-fluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (660 mg, 1.98 mmol) were separated by automated, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 100% acetonitrile at a flow rate of 20 mL/min with. The fractions containing the second peak were combined and concentrated in vacuo, affording a white solid (270 mg, 82% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 330 mg one peak (99.9%) with a retention time of 3.894 minutes; [α]D25=+490° (c=0.0102 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.98 Hz, 3 H) 5.66 (q, 1 H) 6.69 (d, J=7.50 Hz, 2 H) 6.72 (s, 1 H) 6.83 (ddd, J=8.15, 2.46, 1.03 Hz, 1 H) 7.09 (m, 1 H) 7.16 (t, J=7.89 Hz, 1 H) 7.37 (m, 2 H) 7.44 (m, J=7.37, 7.37, 1.81 Hz, 1 H) 7.96 (d, J=7.50 Hz, 1 H) 8.00 (dd, J=8.79, 6.21 Hz, 1 H) 9.66 (s, 1 H); MS (ES1) m/z 334 ([M+H]+); MS (ESI) m/z 332 ([M−H]−); HRMS: calcd for C21H16FNO2, 333.1165 (M), 334.12379 ([M+H]+); found (ESI+), 334.12344.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:12][CH:13]1C(=O)OC(C)(C)[O:15][C:14]1=O)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>CCCCCCC>[C:1]([O:5][C:6]([N:7]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:8]1[CH:9]([CH3:11])[CH3:10])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](CC1C(=O)OC(C)(C)OC1=O)NC(=O)OC(C)(C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
In a 3 L, one-necked flask (equipped with a magnetic stir bar and a condenser with nitrogen inlet) was charged (S)-[1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-2-methyl-propyl]-carbamic acid, tert-butyl ester prepared in Step B above (147 g, 0.446 mol) and toluene (1.4 L). The reaction mixture was heated to reflux for 4 h then cooled to room temperature and concentrated in vacuo to yield crude product as a residual oil. The crude product was dissolved in heptane (˜200 mL) and loaded onto a Biotage 75 L (800 g silica gel) and eluted with heptanes (1 L), 1:9 (7 L), and 1:3 ethyl acetate-heptane (2 L) to yield the product as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[NH:25][N:24]=1.N=C=N>CN(C=O)C>[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:8]([C:7]3[CH:6]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)[CH2:5][C:4](=[O:21])[NH:3][C:2]=3[CH3:1])=[O:9])[CH:30]=2)[NH:25][N:24]=1
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Yield: 12.9 %

Procedure:
The product from Example 1, Step 2 (100 mg, 0.36 mmol, 1.0 equiv) was combined with 3-chloro-1H-indazol-5-amine (90 mg, 0.53 mmol, 1.5 equiv) and PS-carbodiimide resin (0.994 mmol/g loading, 564 mg, 0.53 mmol, 1.5 equiv) in 5 mL of DMF and reacted overnight at room temperature. The reaction mixture was filtered and washed alternately with MeOH and CH2Cl2 (twice), then with diethyl ether. The filtrate was concentrated en vacuo and redissolved in ethyl acetate. The solution was washed with 0.5 N HCl, 0.5 N NaOH, and satd. NaCl. The organic layer was concentrated en vacuo. The residue was triturated with methylene chloride/methanol/ethyl acetate to provide 20 mg (13%) of the title compound as a light pink powder. MS (ES+) m/e 431 [M+H]+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].N1C=CC=CC=1.[C:11](Cl)(=[O:22])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[CH3:3][O:2][NH:4][C:11](=[O:22])[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CONC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
Methoxylamine hydrochloride (1.00 g, 12.0 mmol) was suspended in a mixture of dry pyridine (0.97 mL, 12.0 mmol) and dichloromethane (24 mL), and a solution of 4-nitrophenyl chlorocarbonate (2.41 g, 12.0 mmol) in dichloromethane (12 mL) was added over 30 min with stirring. The resulting heavy white suspension was warmed to reflux, refluxed for 6 h, and cooled to room temperature. The suspension was diluted with dichloromethane and washed with 1M HCl, keeping the emulsion with the aqueous layer, and the aqueous layer was re-extracted with dichloromethane. The combined organic phase was washed with water, saturated aqueous sodium bicarbonate and brine, keeping any emulsions with the aqueous layer, and then dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography (90 g silica gel, 20-40% EtOAc/hexanes) to give the title compound (0.92 g) as a white crystalline solid. A second set of less pure product fractions was isolated to give additional product (0.21 g) as a white solid.