Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[N:6][CH:7]=2)[CH2:41]1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: CN(C)[C@@H]1CCNC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CC[C@@H](N(C)C)C5)cn3)C4)n[nH]c2c1
Yield: 38.2 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and (R)-3-dimethylaminopyrrolidine, (35 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method C to afford (35 mg, 38%) of the title compound as white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:30]1([CH2:33][C@H:34]([NH2:41])[C:35]2[N:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH2:32]C1>>[CH:33]1([CH:34]([NH:41][C:12]([C:10]2[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:35]2[N:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH2:30][CH2:32]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(C(F)(F)F)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e=397.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C>[NH2:11][C:9](=[O:10])[C@@H:7]([NH:8][C:27]([C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-Iodo-(L)-phenylalaninamide (2 g), (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (2.4 g) and disopropylethylamine (3 mL) were dissolved in DMF (10 mL) and to the solution was added 2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.3 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (200 mL) then washed with water (250 mL) and brine (4×250 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with ethyl acetate to give the sub-title compound (2.88 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([C:13]2[CH:14]=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[O:12])[CH2:10][CH2:9]1.Cl>ClCCl>[C:14]([CH:13]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:12])[C:17]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([F:27])([F:29])([F:25])([F:26])[F:28])=[CH:22][CH:23]=1)=[O:16])#[N:15]
Reactant: O=C(c1cnoc1-c1ccc(S(F)(F)(F)(F)F)cc1)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1

Procedure:
Triethylamine (0.73 g) was added to a stirred solution of 4-cyclopropylcarbonyl-S-(4-pentafluorosulphanylphenyl)isoxazole (Compound 2, 0.4 g) in dichloromethane. After 16 hours the solution was washed (2M hydrochloric acid), dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography eluting with ethyl acetate/hexane to give a residue which was suspended in dichloromethane and shaken with hydrochloric acid until dissolved. The organic phase was evaporated and triturated with hexane to give 2-cyano-3-cyclopropyl-1-(4-pentafluorosulphanylphenyl)propan-1,3-dione as a white solid (Compound 3, m.p.108-110° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F:15][C:16]([F:33])([F:32])[C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[CH2:30]O)=[O:24])[CH2:19][CH2:18]1.N1CCC[C@@H]1CO>>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([O:1][CH2:30][C@H:26]2[CH2:27][CH2:28][CH2:29][N:25]2[C:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([C:16]([F:32])([F:15])[F:33])[CH2:18][CH2:19]2)=[O:24])[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=1
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO
Reactant: CCOC(=O)c1ncc(OC)cc1O
Agent: OC[C@H]1CCCN1
Product: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using ethyl 3-hydroxy-5-methoxypicolinate (EXAMPLE 31 Step 2) and [(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (EXAMPLE 31 Step 1) instead of 5-chloropyridin-3-ol and (R)-pyrrolidin-2-ylmethanol.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC[CH2:43][CH2:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:43][CH2:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(O)(CC)CCCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.5 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (84.3 mg, 0.145 mmol), 6-bromo-3-ethyl-3-hexanol (152 mg, 0.725 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=2:1, developed twice) to give 76.4 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 6-bromo-3-ethyl-3-hexanol.
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:11]([CH2:30][C:31](OCC)=[O:32])(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CS(O)(=O)=O>[F:10][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[C:8]=1[OH:9])[O:4][C:31](=[O:32])[CH:30]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Oc1ccc(F)c(O)c1F
Reactant: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCCCCCCCCc1cc(=O)oc2c(F)c(O)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
A mixture of 2,4-difluororesorcinol (Compound 4, 0.15 g, 1.0 mmol) and ethyl stearoylacetate (354 mg, 1.03 mmol) in methanesulfonic acid (4 mL) is stirred at room temperature overnight. The reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with brine (1×) and dried over sodium sulfate, then concentrated to 0.67 g of a pale brown solid, which is purified by silica gel chromatography to give 49 mg of Compound 30 as a colorless powder: Rf =0.64 (EtOAc/hexanes 3:2). 1H NMR (CDCl3) δ 7.12 (dd, 1H), 6.22 (s, 1H), 1.7-0.7 (m, 70H). 19F NMR (CDCl3) Φ 139.8 (t, 1F), 153.5 (d, 1F).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][Cl:12])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClCc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a mixture of (6-chloro-pyridine-2-yl)-methanol (200 mg, 1.39 mmol) described in Manufacturing Example 52-1-1 and toluene (3 mL) was added thionyl chloride (152 μL, 2.09 mmol) on an ice bath, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (163.2 mg, 73%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH:39]2[CH2:44][CH2:43][CH:42]([C:45]3[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]4[C:46]=3[CH2:47][N:48]([CH3:56])[C:49]4=[O:55])[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([C@H:39]2[CH2:40][CH2:41][C@H:42]([C:45]3[CH:53]=[CH:52][C:51]([NH:54][C:2]4[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]5[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=5[O:28][CH3:29])[N:3]=4)=[C:50]4[C:46]=3[CH2:47][N:48]([CH3:56])[C:49]4=[O:55])[CH2:43][CH2:44]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCN(C2CCC(c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](N5CCN(C(C)=O)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compounds were prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 4-[4-(4-acetyl piperazin-1-yl)cyclohexyl]-7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 237A). The reaction mixture was purified by MDP. Example 237 was first peak to elute. 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=6.95 Hz, 6 H), 1.50-1.73 (m, 7 H), 2.02 (s, 2 H), 2.12 (s, 3 H), 2.50 (br. s., 2 H), 2.62 (br. s., 3 H), 3.13-3.21 (m, 2 H), 3.22 (s, 3 H), 3.42-3.75 (m, 4 H), 3.93 (s, 3 H), 3.99-4.10 (m, 4 H), 4.38 (s, 2 H), 6.90 (dt, J=8.08, 2.15 Hz, 1H), 6.94 (t, J=2.02 Hz, 1 H), 7.34 (d, J=8.84 Hz, 1 H), 7.63 (s, 1 H), 8.28 (d, J=7.58 Hz, 1H), 8.40 (s, 1 H), 8.64 (d, J=8.59 Hz, 1 H), 10.51 (s, 1 H). MS (ES+): m/z 788.31 [MH+] (TOF, polar). Example 238 eluted afterwards: 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=7.07 Hz, 6 H), 1.87 (d, J=4.04 Hz, 2 H), 1.91-2.03 (m, 2 H), 2.12-2.25 (m, 7 H), 2.84 (br. s., 2 H), 3.21 (s, 3 H), 3.23-3.33 (m, 4 H), 3.86 (s, 3 H), 3.93 (br. s., 2 H), 4.04 (qdd, J=7.31, 7.31, 7.31, 7.14, 1.77 Hz, 4 H), 4.38 (s, 2 H), 6.94-7.00 (m, 2 H), 7.36 (d, J=7.83 Hz, 1 H), 7.71 (br. s., 1 H), 8.23 (br. s., 2 H), 11.20 (br. s., 1 H). MS (ES+): m/z 788.31 [MH+] (TOF, polar).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH:28]2[CH2:33][C:32](=[O:34])[NH:31][CH:30]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:29]32[C:50]2[C:45](=[CH:46][C:47]([Cl:51])=[CH:48][CH:49]=2)[NH:44][C:43]3=[O:52])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:51][C:47]1[CH:46]=[C:45]2[NH:44][C:43](=[O:52])[C:29]3([CH:28]([C:22]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=4[N:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH2:33][C:32](=[O:34])[NH:31][CH:30]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:50]2=[CH:49][CH:48]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 2 h
Yield: 96.6 %

Procedure:
At room temperature, trifluoroacetic acid (2 mL) was added into a solution of racemic (2′S,3S,4′R)-4′-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (280 mg, 0.43 mmol) in DCM (10 mL). After stirred for 2 h, the mixture was concentrated. The residue was dissolved in EtOAc, washed with 1 N NaOH and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (230 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C.O>[F:29][C:24]1[C:23]([C:12]2[CH:13]=[C:14]3[C@:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]4[CH:3]=[C:2]([C:43]5[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NC1=NC2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1ccnc(F)c1
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@]2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 100 °C

Procedure:
To a vial was added (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (50 mg, 0.122 mmol), potassium phosphate (78 mg, 0.365 mmol), 2-fluoropyridin-4-ylboronic acid (34.3 mg, 0.243 mmol), and 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (4.31 mg, 6.09 μmol), dioxane (609 μL) and water (203 μL). The reaction mixture was purged with N2 gas and heated at 100° C. in microwave reactor for 15 mins. It was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated in vacuo to give the crude material. The crude was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 25% to 40% to 80% DCM/MeOH (90/10) in DCM, to provide (R,E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid. MS m/z=472.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1 H) 2.24-2.41 (m, 1 H) 3.39 (dt, J=11.25, 5.62 Hz, 2 H) 4.37-4.47 (m, 1 H) 4.47-4.61 (m, 1 H) 6.13 (br. s., 2 H) 7.41 (d, J=8.31 Hz, 1 H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1 H) 7.60 (dt, J=8.39, 1.87 Hz, 1 H) 7.67-7.75 (m, 2 H) 7.89-7.95 (m, 1 H) 8.03-8.16 (m, 2 H) 8.25 (dt, J=4.82, 1.50 Hz, 1 H) 8.38 (d, J=5.28 Hz, 1 H) 8.66-8.77 (m, 1 H).
Reaction SMILES: [Cl-].[CH3:2][NH:3][CH3:4].[C:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)(O)=[O:6]>CN(C)C=O>[CH3:2][N:3]([CH3:4])[C:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6]
Reactant: CNC
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-adamantanol obtained by the method of Example 2 was dissolved in 10 ml of N,N-dimethylformamide (DMF). To the mixture, 15 mmole of tionyl chloride was added dropwise over 30 minutes while heating the mixture to the reflux temperature so as to begin to reflux at about the time the addition is finished. After refluxing for 2 hours, the mixture was cooled. To the mixture, 25 mmole of dimethylamine was added dropwise over 30 minutes while keeping the temperature of the solution at 10° C. or below, and the mixture was stirred for another 2 hours. As a result, the conversion of 1-carboxy-3-adamantanol was 99%, and 1-(N,N-dimethylcarbamoyl)-3-adamantanol (yield 95%) was formed.
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:2]([C:6]([N:8]([CH3:41])[C@H:9]([C:27]([NH:29][CH2:30][C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:28])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:26])[NH:15][S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.[Pd]>[NH:1]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C@@H:2]([C:6]([N:8]([CH3:41])[C@H:9]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:26])[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Yield: 78 %

Procedure:
A solution of Boc-D-Val-NMeArg(Tos)-Gly-OBzl (4.50 g, 6.53 mmol) in 80 ml of methanol was purged with nitrogen gas, 1.30 g of 10% Pd/C was added, and hydrogen gas was passed over the reaction. After 1 hour the catalyst was removed by filtration through a bed of celite, and the solvent removed under reduced pressure. The resulting solid was triturated with ether, filtered, and washed with petroleum ether to provide Boc-D-Val-NMeArg(Tos)-Gly (3.05 g, 78%); 1H NMR (D6 -DMSO) d 7.90 (br t, 1H), 7.65 (d, 2H), 7.30 (d, 2H), 7.00 (d, 1H), 6.85 (br d, 1H), 6.60 (br s, 1H), 5.00 (dd, 1H), 4.15 (t, 1H), 3.70 (m, 2H), 3.05 (m, 2H), 2.90 (s, 3H), 2.35 (s, 3H), 1.90 (m, 2H), 1.55 (m, 1H), 1.35 (s, 9H), 1.25 (m, 2H), 0.80 (br t, 6H); FAB-MS: [M+H]=599.45.
Reaction SMILES: [CH:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=O)([CH2:3][CH3:4])[CH3:2].[CH:16]([NH:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:18])[CH3:17].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([N:19]([CH:16]([CH3:18])[CH3:17])[NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CCC(C)c1ccccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)c1ccccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 36.4 %

Procedure:
A solution of (2-sec-butyl-phenoxy)-acetic acid (193 mg, 0.93 mmol), and benzoic acid N′-isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (113 mg, 33%). MS m/e 369.32 (M+H+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(OC(C)C)(=O)C>[Cu].CN(C=O)C>[F:15][C:9]([F:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccccn1
Agent: [Cu]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
2-Bromopyridine (20 g), ethyl bromodifluoroacetate (27.2 g) and DMF (120 mL) were added and stirred for 10 minutes under nitrogen. Copper powder was added to the reaction mixture and heated to 70-80° C. for 45 minutes. The reaction mixture was cooled to RT and 400 mL of isopropyl acetate (IPAc) was added. The reaction mixture was quenched with the aqueous potassium dihydrogen phosphate at 0-10° C. and stirred for 30 minutes. The reaction mixture was filtered off and the residue obtained was washed with ethyl acetate. The organic layer was collected and washed with brine solution and dried over sodium sulphate then distilled under vacuum. (Crude weight=20 g).
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O.P([O-])(O)(O)=[O:25].[Na+]>ClCCl>[CH2:1]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[O:25][CH2:22]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: C=CCCCCCCCCCOCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C(=COCc1ccc2c(c1)OCO2)CCCCCCCC1CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 11.0 g. (0.036 mole) of 10-undecenyl piperonyl ether and 5.0 g. (0.036 mole) of sodium dihydrogen phosphate monohydrate in 100 ml. of dichloromethane, was added 7.6 g. (0.036 mole) of m-chloroperbenzoic and dissolved in 200 ml. of dichloromethane. After stirring at ambient temperature for 24 hours, the mixture was filtered and washed with an aqueous sodium bicarbonate solution. After drying the dichloromethane solvent was removed by evaporation. The crude product obtained in this way was purified by passing through a silica gel chromatographic column using first a 5% ether in hexane eluent and then a 50% ether in hexane eluent to recover the 10,11-epoxyundecenyl piperonyl ether which weighed 5 g. An infrared spectra had strong adsorption peaks at 3.4, 3.5, 6.7, 6.95, 7.9-8.0, 9.1, 9.6, 10.8 and 12.4 microns.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:28][CH:27]=[CH2:26])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 55 °C
Yield: 105.7 %

Procedure:
A solution of 1,3-di-N-butyl xanthine (10 g, 38 mmol) in anhydrous DMF (80 ml) was treated with K2CO3 (5.2 g, 38 mmol) followed by allyl bromide (3.6 ml, 42 mmol). The mixture was heated at 55° C. under nitrogen for 18 hours. After cooling to rt the mixture was partitioned between water and EtOAc. A few mls of 2M HCl(aq) was added to aid separation. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated to afford the title compound as an off-white solid (12.23 g, 106%). m/z 305.3 [MH+].