Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[CH:7]=1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(-c4ccsc4)c3)cc21

Procedure:
Prepared from 6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-thiophene boronic acid according to procedure B. A brownish-orange solid: mp 200-203° C.; 1H-NMR (CDCl3) δ8.62 (s, 1H), 7.53 (q, 1H, J=1.4 Hz), 7.50 (d, 1H, J=1.5 Hz), 7.49 (d, 1H, J=2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, J=1.8 Hz), 7.27-7.24 (m, 2H), 7.15 (dt, 1H, J=5.8, 2.0 Hz), 694 (d, 1H, J=8.2 Hz), 1.80 (s, 6H); MS ((−)APCI) [M−H]− @ m/z 352. Anal. Calc. For C20H16FNO2S 0.50 H2O: C, 66.28; H, 4.73; N, 3.87. Found: C, 66.54; H, 5.03; N, 3.52.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][Cl:9].C([O-])([O-])=[O:12].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][Cl:9]
Reactant: O=C([O-])[O-]
Reactant: ClCc1c(Cl)cncc1Cl
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a solution of 3,5-dichloro-4-chloromethyl-pyridine (0.55 g, 2.8 mmol) in DCM (10 mL) 3-methyl-benzenecarboperoxoic acid (2.9 g, 16.8 mmol) was added. After stirring for 50 h at room temperature, saturated aqueous Na2CO3 solution (20 mL) and DCM (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (elution with EA/hexane 1:2) to give the title compound. MS (m/z): 214.2 [M+H+].
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8](Cl)=[O:9])=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:14]=1.CCN(C(C)C)C(C)C>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:8]([C:6]2[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:9])=[C:15]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:14]=1
Reactant: COc1ccc(N)c(N2CCCCC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 60 %

Procedure:
Using a procedure similar to Example 1, step (e), 5-cyano-furan-2-carbonyl chloride (66 mg, 0.43 mmol) was allowed to react with 4-methoxy-2-piperidin-1-yl-phenylamine (67 mg, 0.32 mmol, as prepared in the previous step) in the presence of DIEA (164 μL, 0.940 mmol) for 2 h to afford 62 mg (60%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.49 (br s, 1H) 8.35 (d, 1H, J=8.9 Hz), 7.27-7.22 (m, 1H), 6.76 (d, 1H, J=2.7 Hz), 6.71 (dd, 1H, J=2.8, 8.9 Hz), 3.81 (s, 3H), 2.85-2.83 (m, 4H), 1.84-1.78 (m, 4H), 1.66-1.65 (m, 2H); Mass spectrum (ESI, m/z): Calcd. for C18H19N3O3, 326.1 (M+H), found 326.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH2:23][CH2:22][CH2:21][C:18]=3[CH:19]=2)[NH:14][C@@H:13]([CH3:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[CH2:36]([O:35][C:33]([N:14]1[C:15]2[C:20](=[CH:19][C:18]3[CH2:21][CH2:22][CH2:23][C:17]=3[CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:12][C@@H:13]1[CH3:24])=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc3c(cc2N1)CCC3
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-(2-methyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinolin-4-yl)-carbamic acid benzyl ester (Example 1A) (2.0 g, 4.9 mmol) in anhydrous dichloromethane (50 mL) was added pyridine (1.0 mL). The mixture was cooled to 0° C., and ethyl chloroformate (1.0 mL) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 4 h. The reaction mixture was washed twice with 25 mL of 2N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 15% ethyl acetate/hexanes as eluent afforded the title product (500 mg). 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.2 (t, 3H), 4.2 (m, 2H), 5.2 (s, 2H), 7.0 (s, 1H), 7.3 (s, 1H), 7.4 (m, 5H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[C:30]([F:31])=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Cl:21][C:22]1[C:30]([F:31])=[C:29]2[C:25]([C:26]([S:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][N:28]2[C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccc(S)c1
Reactant: CCCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 0.83 h
Yield: 60.7 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (66 mg, 0.36 mmol) in CH2Cl2 (5 mL) under inert atmosphere was added NCS (48.2 mg, 0.36 mmol) at RT and stirred for 50 min. To this, compound 3 (100 mg, 0.36 mmol) was added at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 9% EtOAc/Hexanes to afford compound 4 (100 mg, 61%) as a colorless syrup. 1H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H), 7.77-7.76 (m, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 7.27-7.24 (m, 3H), 7.15-7.12 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.15 (t, J=7.0 Hz, 2H), 1.98-1.94 (m, 2H), 1.35 (t, J=7.5 Hz, 3H), 0.98 (t, J=7.0 Hz, 3H); LC-MS: 94.6%; m/z 458.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.91 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(OCC)C>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)c1nc(NC(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4.3 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile in 125 ml of diethyl ether was added dropwise 2.6 grams of diethylamine. Upon complete addition, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water. The diethyl ether layer was separated and dried over magnesium sufate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from methylcyclohexane to give 2.5 grams of 4-chloro-6-diethylamino-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 74°-76°.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1([C:9]2[C:10](F)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:33]>CN1C(=O)CCC1>[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][C:10]2[C:9]([C:3]3([CH:2]([F:16])[F:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: Fc1ncccc1C1(C(F)F)CCOCC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2ncccc2C2(C(F)F)CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 175 °C

Procedure:
To a solution of 3-(4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)-2-fluoropyridine (0.1 g, 0.432 mmol) in NMP was added cesium carbonate (0.282 g, 0.865 mmol) and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.155 g, 0.649 mmol). The resulting mixture was heated to 175° C. overnight. Purification by prep-plate TLC (5% MeOH/DCM & 75% EtOAc/hexane) produced product. MS (ESI, pos. ion) m/z: 450 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:9])[CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([CH:30]=O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][C:20](=[O:19])[NH:25][C:24]=3[CH:26]=2)[CH2:3][CH2:4]1)=[O:9]
Reactant: NC1CCC(C(=O)c2nc3ccccc3s2)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Product: O=C1COc2ccc(CN[C@H]3CC[C@H](C(=O)c4nc5ccccc5s4)CC3)cc2N1

Procedure:
The title compound was prepared according to the same protocol as for example 1, step 1.c, using however (4-amino-cyclohexyl)-benzothiazol-2-yl-methanone (0.3 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.3 mmol). 40 mg (28%) of the title compound (a yellowish solid) were obtained.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25]2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Yield: 85.5 %

Procedure:
Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (×2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2-trityl-2,3-dihydro-1H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCl3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:33])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH:34]([C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[C:39]([CH:46]([CH3:48])[CH3:47])[C:38]=1[S:49](Cl)(=[O:51])=[O:50])([CH3:36])[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:33][S:49]([C:38]2[C:39]([CH:46]([CH3:47])[CH3:48])=[CH:40][C:41]([CH:43]([CH3:45])[CH3:44])=[CH:42][C:37]=2[CH:34]([CH3:36])[CH3:35])(=[O:51])=[O:50])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(OS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reaction time: 1 h
Yield: 92 %

Procedure:
The intermediate from Step 1 above (500 mg, 0.98 mmol) was dissolved in DCM (15 mL) at ambient temperature. DMAP (7.3 mg, 0.06 mmol), and TEA (16 ml, 11 mmol) were added to the solution, followed by 2,4,6-triisopropylbenzenesulfonyl chloride (454 mg, 1.5 mmol). After 1 h the reaction had gone to completion, the crude mixture was concentrated, and then purified by flash chromatography (SiO2, 10% EtOAc—CHCl3), affording 690 mg (92%) of 5-acetylamino-7-(2,4,6-triisopropyl-benzenesulfonyloxy)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidin-2-one as a foaming white solid 17: 74.5-76.3° C.; Rf=0.7 (SiO2, 20% EtOAc—CHCl3); 1H (400 MHz, d6-DMSO) δ 10.83 (s, 1H), 7.39 (s, 2H), 6.03 (d, J=4.0, 1H), 5.91-5.96 (m, 1H), 5.69 (t, J=6.4, 1H), 4.30-4.70 (m, 1H), 4.22-4.26 (m, 1H), 4.16-4.20 (m, 1H), 3.90-4.00 (m, 2H), 2.97-3.01 (m, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 1.88 (s, 3H), 1.17-1.25 (m, 18H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5]([NH:7][C@@H:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5]([NH:7][C@@H:8]1[O:16][CH2:15][C@@H:13]([O:14][C:23](=[O:25])[CH3:24])[C@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@H:9]1[O:10][C:9](=[O:10])[CH3:8])=[O:6]
Reactant: O=NN(CCCl)C(=O)N[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1NC(=O)N(CCCl)N=O
Yield: 29.4 %

Procedure:
1-(2-chloroethyl)-1-nitroso-3-(β-D-xylopyranosyl) urea (99 mg) was acetylated with acetic anhydride and pyridine in the same manner as that used in Example 1(b). Crystallization from a mixture of chloroform and n-propanol yielded the titled compound (42 mg). Yield 29.4%. mp. 124.5°-125° C (with decomposition). [α]D17 -19.0° (c 0.9, chloroform).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][N:35]4[CH2:40]COC[CH2:36]4)=[CH:28][CH:27]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:25])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:41]N(CC#C)C.C(NC(C)C)(C)C>O1CCCC1.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.[Cu]I>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][N:35]([CH3:36])[CH3:40])=[CH:28][CH:27]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([O:22][CH3:41])=[O:21])=[C:16]([CH3:25])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: C#CCN(C)C
Reactant: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)ccc1OCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a degassed solution of the ester (486 mg, 0.877 mmol; prepared as described in example 38), 1-(N,N-dimethylamino)prop-2-yne (150 mg, 1.80 mmol) and diisopropyl amine (0.589 mL, 4.24 mmol) in anhydrous tetrahydrofuran (12 mL), bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol) and copper(I) iodide (14.0 mg, 0.074 mmol) were added. The reaction mixture was stirred at ambient temperature for 6 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: COC(=O)C(OC)(OC)C(=O)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OC)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
In a manner similar to the procedure described in Example I, 3,5-dichloroaniline was reacted with methyl chlorocarbonyl(dimethoxy)acetate, prepared as described in Example LXV Part A, employing triethylamine as the acid acceptor in methylene chloride solution. The methyl 3-[(3,5-dichlorophenyl)amino]-2,2-dimethoxy-3-oxopropanoate product (2.31 grams, 0.007 mole) was obtained as colorless crystals having a melting point of 160° C.-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[N:18][C:19]=1[O:20][CH3:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:22][C:16]2[CH:17]=[N:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cnc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1OC
Yield: 65.6 %

Procedure:
The title compound (542 mg, 1.64 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 5,6-dimethoxypyridin-3-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:16])[CH3:15])=[CH:4]1)[CH3:2].[CH2:17]([N:19]1C2C(=CC=C(OC)C=2)C=C1)C.COC(OC)N(C)C.N1CCCC1.Cl.NO>O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[O:16][N:19]=[CH:17][CH:15]=2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(C)=O)c2ccc(OC)cc21
Reactant: CCn1ccc2ccc(OC)cc21
Agent: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: C1CCNC1
Solvent: O
Product: CCn1cc(-c2ccno2)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 66 %

Procedure:
1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, was heated with 1.5 mL of dimethylformamide dimethylacetal and 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamide dimethylacetal was then concentrated in vacuo. The residue was redissolved in 1.25 mL of EtOH and 250 μL of H2O, and was treated with hydroxylamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h. Partitioning between H2O and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) gave 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole as a white solid (72 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1.[OH:24]/[N:25]=[C:26](\Cl)/[C:27]1[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:29][N:28]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]4([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[O:24][N:25]=[C:26]([C:27]5[C:31]([C:32]([F:35])([F:33])[F:34])=[C:30]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:29][N:28]=5)[CH:12]4[CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(c2ccc3c(n2)CCC=C3N2CCOCC2)O1
Reactant: O/N=C(\Cl)c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(c2ccc3c(n2)CCC2C(c4noc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholine (Preparation 15F, 0.194 g, 0.613 mmol) in dichloromethane (2 mL) was added a solution of (Z)—N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride (Intermediate 13, 0.210 g, 0.613 mmol) in dichloromethane (1 mL). The reaction mixture was cooled to 0° C., and triethylamine (0.093 mL, 0.674 mmol) was added dropwise over 2 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (15 mL), dried over anhydrous sodium sulfate, and concentrated to give the morpholino-intermediate, 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(5-phenyl-4-(trifluoromethyl)-isoxazol-3-yl)-3a,4,5,9b-tetrahydroisoxazolo[5,4-f]quinoline, as an orange oil. To the oil was added dichloroethane (3 mL) and TFA (0.071 mL, 0.920 mmol), and the reaction mixture was heated at 80° C. for 60 min. The reaction mixture was stirred overnight at room temperature. Additional TFA (0.071 mL, 0.920 mmol) was added, and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (15 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by trituration with methanol with sonication afforded 44 mg of a 3:7 mixture of 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinolin-7-yl)ethane-1,2-diol and 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinoline as a light brown solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH2:9]1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[F:36][C:21]([F:20])([F:37])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([N:8]2[CH2:9][CH:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH2:11]2)=[O:31])[N:23]=1
Reactant: N#Cc1ccc(C2CNC2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C2CN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)C2)nc1
Yield: 47 %

Procedure:
This compound was synthesized from 6-(azetidin-3-yl)nicotinonitrile TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (70 mg, yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 9.06 (m, 1H), 8.30-8.29 (m, 2H), 8.21-8.19 (d, J=7.8 Hz, 1H), 7.96-7.94 (d, J=7.8 Hz, 1H), 7.74-7.70 (t, J=7.7 Hz, 1H), 7.63-7.61 (d, J=8.1 Hz, 1H), 4.76-4.72 (m, 1H), 4.52-4.46 (m, 2H), 4.25-4.18 (m, 2H). MS (ESI) m/z: Calculated for C19H12F3N5O2: 399.09. found: 400.2 (M+H)+
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>C1COCC1.Cl>[CH2:23]([O:22][C:19](=[O:21])[CH:20]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[C:7]1[CH:17]=[CH:18][C:4]([Br:3])=[CH:5][CH:6]=1)[CH3:24]
Reactant: CCOC(C)=O
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A solution of triethyl phosphonoacetate (26.8 g, 120.0 mmol) in dry THF (100 mL) was added at 0° C. over a period of 25 min. to a stirred suspension of sodium hydride (60% in oil, 4.8 g, 120.0 mmol) in dry THF (100 ml). After stirring at 0° C. for 30 min. a solution of 4,4′-dibromobenzophenone (20.4 g, 60.0 mmol) in dry THF (200 ml) was added and the mixture slowly warmed to room temperature, and stirring continued for 48 h. The reaction mixture was diluted with 1N hydrochloric acid (400 ml) and ethyl acetate (100 ml). The organic phase was separated, and the aqueous phase further extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with water (300 ml×3), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel (15% ethyl acetate in n-heptane eluent) to give 24.5 g (99%) 3,3-bis-(4-bromophenyl)-acrylic acid ethyl ester as an off-white amorphous solid.