Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][C@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
3-Bromo-4-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 10.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (32.2 mg, 0.260 mmol), Pd(PPh3)2Cl2 (9.11 mg, 0.013 mmol) and Na2CO3 (55.0 mg, 0.519 mmol) were added to a MW vial and treated with a mixture of DME (551 μL), water (157 μL) and EtOH (79 μL). Vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 54.1 mg, 0.078 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, isocratic 25% in 9 min.) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=0.83 min, m/z=462.1 [M+H]+, m/z=460.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=10.76, 4.16 Hz, 2H) 3.26 (dd, J=10.51, 4.89 Hz, 2H) 3.98 (t, J=3.91 Hz, 2H) 4.89 (br. s, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:24][NH:23][C:10](=[O:11])[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(O)OC(=O)C(c2ccccn2)=C1c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
A mixture of 0.67 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-pyridyl)-2(5H)-furanone, 0.25 g of hydrazine monohydrate and 8 ml of 1-butanol was stirred for 5 hours on an oil bath of 110° C. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The resultant solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure, to obtain 0.32 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)-2H-pyridazin-3-one.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N+:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)#[C-:35]>>[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][CH:36]([N+:34]#[C-:35])[CH2:37][CH2:38]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: [C-]#[N+]C1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: [C-]#[N+]C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-isocyano-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-Isocyano-piperidine following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-[(3R,3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (34 mg, 0.052 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature. After 1 hour, the reaction mixture was evaporated to an oil, dissolved in EtOH (1 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile/water+0.05% TFA flush. The desired fractions were lyophilized to give the title compound as a solid. LC-MS: calculated for C28H26ClN3O5 519.16 observed m/e: 520.22 (M+H)+ (Rt 0.74/2 min); 1H NMR δ (ppm) (CD3OD): 7.87 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.57 (qt, 1H), 5.01 (t, 1H), 4.60 (t, 1H), 4.16 (q, 2H), 4.10 (dd, 1H), 4.00-4.06 (m, 2H), 3.53 (dd, 1H), 2.71 (dd, 1H), 2.59 (m, 1H), 2.51 (dd, 1H) and 1.27 (t, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.CCN(CC)CC>CCO>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 150 °C
Yield: 90.1 %

Procedure:
A mixture of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (200 mg, 1.09 mmol), 4,6-dichloropyrimidine (240. mg, 1.61 mmol) and Et3N (0.380 mL, 2.73 mmol) in EtOH (3.00 mL) was heated to 150° C. for 15 min using MWI. The crude mixture was purified via silica gel chromatography eluting with a gradient of 0 to 15% MeOH in DCM to afford the title compound (255 mg, 90%). LC/MS: Rt=1.13 min, ES+ 260. (AA standard).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][CH:5]([N:8]([C@H:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[C:9](=[O:16])[C:10]([CH3:15])([CH3:14])[CH:11]([OH:13])[CH3:12])[CH2:4][CH2:3]1.[C:23]([N:27]1[CH2:31][C@@H:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C@H:29]([C:39](O)=[O:40])[CH2:28]1)([CH3:26])([CH3:25])[CH3:24]>>[ClH:38].[C:23]([N:27]1[CH2:31][C@@H:30]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[C@H:29]([C:39]([N:19]2[CH2:20][CH2:21][C@H:17]([N:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:1])([CH3:22])[CH2:3][CH2:4]3)[C:9](=[O:16])[C:10]([CH3:14])([CH3:15])[CH:11]([OH:13])[CH3:12])[CH2:18]2)=[O:40])[CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: CC(O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCNC1
Product: CC(O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(Cl)cc2)C1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in Step F, G of Example A1, using N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethyl-N-[(3S)-pyrrolidine-3-yl]butaneamide (73 mg, 0.23 mmol) prepared in Step B and (3S,4R)-1-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (232 mg, 89%).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH:9](O)=[O:10].C(OCC)(OCC)OCC.[ClH:22]>O.CC(O)C>[OH2:4].[OH2:10].[ClH:22].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: O=CO
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1nc[nH]c1O
Temperature: 81 °C
Reaction time: 0.55 h

Procedure:
Under the nitrogen atmosphere, 5.00 g of 2-aminomalonamide and 20 mg of formic acid were added to 80 mL of 2-propanol. After heating to 81° C., 17.7 mL of triethyl orthoformate was added to the mixture over 14 minutes. Subsequently, the reaction mixture was stirred for 6 hours and 33 minutes at 83° C. Subsequently, after cooling to 58° C., the reaction mixture was added dropwise with 5 mL of water followed by 4 mL of conc. hydrochloric acid. After cooling the mixture to 20° C., the crystal was collected by filtration and then washed with 20 mL of acetone to give 8.05 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a yellow crystal.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([F:18])([CH3:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1>>[F:18][C:8]1([CH3:17])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:30]#[C:29][C@@:27]([OH:31])([C:24]3[CH:23]=[C:22]([CH3:21])[O:26][N:25]=3)[CH3:28])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CC1(F)COc2ccc(I)cc2-n2nc(C(N)=O)cc21
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2C(C)(F)CO3)no1

Procedure:
Similar to as described in General Procedure G, racemic 9-iodo-4-fluoro-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give a diasteromeric mixture of the titled compound after purification by prep HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 3-methoxy-4-[3-o-tolyl-ureido]phenylacetic acid (0.282 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran (5 ml), under an atmosphere of argon and at 25° C., was treated with powdered molecular sieves 4 Å (0.5 g), 7-(2-ethoxycarbonyl-ethyl)-1,2,3,4-tetrahydro-quinoxaline-1-carboxylic acid tert-butyl ester (0.2 g, Reference Example 3), triethylamine (0,336 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.273 g) and 4-dimethylaminopyridine (7 mg). After stirring at 25° C. for 3 hours the reaction mixture was filtered through a pad of celite and the filter pad was washed three times with ethyl acetate (10 ml). The combined filtrate and washings were washed twice with an aqueous saturated solution of ammonium chloride (20 ml), then with water (20 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (0.483 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound (0.3 g) as a white foamy solid. 1H NMR, 400 Hz, (CD3)2SO: δ1.2 (t, 3H); 1.5 (s, 9H); 2.3 (s, 3H); 2.65 (t, 2H); 2.9 (t, 2H); 3.65 (t, 2H); 3.85 (m, 7H); 4.1 (q, 2H); 6.7 (very broad s, 2H); 7.2 (m, 2H); 7.5 (very broad s, 1H); 7.65 (broad s, 1H); 7.8 (d, J=8 Hz, 1H); 8.05 (broad d, J=8 Hz, 1H); 8.5 (s, 1H); 8.6 (broad s, 1H). MS (CI, NH3): MNH4+ 648, MH+ 631.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH:8]2[CH2:16][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]2[CH2:16][N:11]3[CH2:12][CH2:13][N:14]([C:22]4[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=4)[CH2:15][C@@H:10]3[CH2:9]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4cncc(Cl)n4)CCN3C2)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of 0.500 g (2.00 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 3), 1.49 g (10.0 mmol) of 2,6-dichloropyrazine, and 0.508 g (4.79 mmol) of sodium carbonate in 50 mL of isoamyl alcohol was heated to reflux for 16 hours. The reaction was cooled to ambient temperature, the solvent removed in vacuo, the residue taken up in ethyl acetate and water, the pH was adjusted to 11 with sodium carbonate and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 ethyl acetate:hexane gave 0.491 g (68%) of the title compound. Mp (.HCl) 209-212° C. HRMS calc'd for C18H21ClFN4O (MH+): 363.1388, found: 363.1384.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.S(=O)(=O)(O)[OH:26]>C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]([NH2:16])=[O:26])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1CN1CC2COCCN2c2nc(Cl)ncc21
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1CN1CC2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-((2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile (PREPARATION x17, 140 mg, 0.410 mmol) was dissolved in concentrated sulfuric acid (1 mL) and was stirred overnight at room temperature. Following reaction, the mixture was diluted with ethyl acetate and was washed with aqueous saturated NaHCO3 (2×15 mL) and brine (2×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by LC/MS using a gradient of 20-45% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to afford the title compound as a white solid (147 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 2.91-3.05 (m, 2H), 3.10-3.19 (m, 1H), 3.22-3.29 (m, 1H), 3.44-3.49 (m, 1H), 3.63-3.73 (m, 1H), 3.81-3.99 (m, 2H), 4.21-4.29 (m, 1H), 4.36-4.61 (m, 2H), 7.19-7.24 (m, 1H), 7.30-7.50 (m, 5H), 7.78-7.87 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H18ClN5O2, 360.11. found 360.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21](O)=[O:22])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.C(N(C(C)C)C(C)C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51]>CN(C1C=CN=CC=1)C.CS(C)=O.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:4][C:3]=1[C:21](=[O:22])[NH:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: Nc1ccccn1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccn3)n2)CC1
Temperature: 110 °C
Reaction time: 20 h
Yield: 54.9 %

Procedure:
To a mixture of 3-amino-6-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazine-2-carboxylic acid (8.08 g, 24.99 mmol), di(imidazol-1-yl)methanone (4.863 g, 29.99 mmol), DMAP (152.7 mg, 1.250 mmol) and N-ethyl-N-isopropyl-propan-2-amine (8.074 g, 10.88 mL, 62.47 mmol) in DMSO (80.80 mL) was added pyridin-2-amine (4.704 g, 49.98 mmol) and the resulting solution stirred at 110° C. for 20 hours. Water (500 mL) was added and the mixture extracted into EtOAc (3×300 mL), dried and concentrated to give a residue which was triturated with EtOAc and filtered to give the required product as a yellow solid (5.48 g, 55% Yield).
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]1([N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([NH2:13])=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[P:20]([O:35]C1C=CC=CC=1)([O:28]C1C=CC=CC=1)[O:21]C1C=CC=CC=1.C(=O)=O.P([O-])([O-])[O-]>C(#N)C.O.C1C=CC=CC=1>[C:4]1([N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:12])[NH:13][CH:1]([P:20](=[O:21])([OH:35])[OH:28])[CH3:2])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: NC(=O)N(c1ccccc1)c1ccccc1
Reactant: CC=O
Agent: O=C=O
Agent: [O-]P([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)N(c1ccccc1)c1ccccc1)P(=O)(O)O

Procedure:
Freshly distilled acetaldehyde (0.22 mole) is added during 0.5 hr to a stirred solution of 0.1 mole each of 1,1-diphenylurea and triphenyl phosphite in 130g of benzene at 60°C. The solution is warmed at reflux (65°-70° with Dry Ice-cooled condenser) for 1.25 hr, giving a dark brown solution having a small 31P nmr peak at -126.2 ppm for unreacted phosphite and a large product peak at -18.4 ppm (~1:5 areas). The reaction mixture is stripped to 130°/3mm. The residue is diluted with 200 ml of acetonitrile and 10g of H2O, and this solution is warmed at reflux for 3 hr. Solid that separates during warming is recrystallized from acetic acid-water to give a white solid: mp 186°-187° dec; p31 nmr -21.6 ppm; 1H nmr δ10.0 (s, 2, OH), 7.3 (m, 10, C6H5 ), 5.4 (d of d, 1, J = 9 and 5Hz, NH), 4.1 (m, 1, CH), 1.3 (d of d, 3, J = 16 and 7 Hz, CH3); acidity 2.00 equiv/ mole, pK1 = 2.20, pK2 = 8.62.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2)[N:3]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)(=O)C>[CH2:28]([O:19][CH2:16][CH:25]1[CH2:26][CH2:27][CH:22]([C@H:28]2[CH2:10][CH2:11][CH2:2][N:3]2[C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=3)[N:3]=2)[CH2:23][CH2:24]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Reactant: O=Cc1cc2cc(F)c(F)cc2nc1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(COCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-6,7-difluoroquinoline-3-carbaldehyde (4.97 g, 18 mmol), trans-(R)-2-[(4-benzyloxymethyl)cyclohexyl]pyrrolidine (5.39 g, 20 mmol) and potassium carbonate (2.97 g, 21 mol) in toluene (100 mL) and water (10 mL) is stirred and refluxed for 3 hours. The reaction mixture is cooled to room temperature and then diluted with water and ethyl acetate. The organic layer is washed with water, citric acid aq., brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinoline-3-carbaldehyde as a yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13].ClCCl.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[N:33][CH:32]=[CH:31]2>CN(C=O)C>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]([NH:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[N:33][CH:32]=[CH:31]4)=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc2cnccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc2cc(NC(=O)Nc3ccc4cnccc4c3)ccc21

Procedure:
The title compound is prepared using standard methodology as described herein, such as reaction of (D2) with carbonyl diimidazole in a solvent such as dry dichloromethane, and reacting the product with 6-aminoisoquinoline in a solvent such as DMF, with heating.
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Br)(Br)[Br:28]>C1(C)C=CC=CC=1>[Br:28][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: OCc1ccc(OCc2cccc3ccccc23)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1ccc(OCc2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A suspension of sodium ethoxide (924 mg, 13.6 mmol) in DMF was stirred at 0° C. for 10 min. Ethyl 4-hydroxy benzoate (2.26 g, 13.6 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h, then allowed to reach room temp. To this mixture 1-(bromomethyl)naphthalene (2.0 g, 9.0 mmol) was added dropwise [(predissolved in DMF (5 mL)]. Resulting mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue taken up in EtOAc, and washed with brine, water and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and the solvent evaporated off in-vacuo to yield ethyl 4-(naphthalene-1-ylmethoxy)benzoate (1.7 g, 5.55 mmol). This was then dissolved in THF and LiAlH4 (211 mg, 5.55 mmol) was added portionwise, with vigorous stirring. The suspension was stirred at room temperature for 3 h. THF was evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). EtOAc was evaporated off in-vacuo to obtain (4-(naphthalene-1-ylmethoxy)phenyl)methanol (1.3 g, 4.9 mmol) as a crude product. This was used in the next reaction step without further purification. (4-(naphthalen-1-ylmethoxy)phenyl)methanol (1.0 g, 3.8 mmol) was dissolved in toluene (30 mL) and pyridine (305 uL, 3.8 mmol) was added. The solution was cooled to 0° C. PBr3 (359 uL, 3.8 mmol) was added dropwise over 15 min. The mixture was brought up to room temperature and stirred for 1 h. It was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain 1-((4-(bromomethyl)phenoxy)methyl)naphthalene (660 mg, 53%). This intermediate was used in the following reaction.