Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:49][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:45]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:66])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:67][C:68]1[CH:79]=[CH:78][C:71]2[C:72](=O)[O:73]C(=O)[O:75][C:70]=2[CH:69]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:45][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:47][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:66][C:72](=[O:73])[C:71]1[CH:78]=[CH:79][C:68]([Cl:67])=[CH:69][C:70]=1[OH:75])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(=O)c2ccc(Cl)cc2o1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(NC(=O)c4ccc(Cl)cc4O)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 80 °C
Yield: 60 %

Procedure:
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.16 g, 0.174 mmol) and 7-chloro-benzo[1,3]dioxine-2,4-dione (91) (0.2 g, 1.0 mmol) were combined and dissolved in NMP (8 mL). The mixture was heated to 80° C. for 16 h. LC-MS indicated complete reaction at this point. The mixture was diluted with EtOAc (30 mL), washed with water (2×15 mL), saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc in hexane) gave the desired product (92) as a yellow powder upon concentration (0.111 g, 0.103 mmol, 60% yield). LC-MS (ESI): (exact mass: 1073.51) m/e=1074.6 [M+1]+ (100%).
Reaction SMILES: C(O)CCCC/C=C\C/C=C\C/C=C\CCCCC.[CH2:20]([Br:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[Br:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: CCCCC/C=C\C/C=C\C/C=C\CCCCCO
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCBr
Yield: 96 %

Procedure:
From gamma linolenyl alcohol (1d) (143 mg, 0.54 mmol), using the procedure described above for preparation of 1-bromooctadecane (2a), (Z,Z,Z)-1-bromo-6,9,12-octadeca-triene (2d) (170 mg, 96%) was obtained as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19](I)=[CH:20][C:12]1=2)(=[O:10])=[O:9].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:20][C:12]1=2)(=[O:10])=[O:9]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=S(=O)(c1ccccc1Cl)N1CCNc2ncc(I)cc21
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(S(=O)(=O)c3ccccc3Cl)CCN4)cn2)CC1
Yield: 41 %

Procedure:
1-(2-Chlorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow solid (41% yield). M.p. 164-165° C., LCMS: m/z=486.79 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (s, 3H), 2.54 (t, J=5.1 Hz, 4H), 3.39-3.42 (m, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.88 (t, J=4.5 Hz, 2H), 5.17 (bs, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.39-7.45 (m, 1H), 7.51-7.56 (m, 3H), 7.73 (s, 1H), 8.01 (d, J=1.0 Hz, 1H), 8.13 (dd, J=8.6 Hz, 1.0 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1(S[CH2:22][C:23]#[N:24])C=CC=CC=1.Cl>CS(C)=O>[CH3:11][O:10][C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]([CH3:3])=[C:9]([CH2:22][C:23]#[N:24])[CH:8]=1
Reactant: N#CCSc1ccccc1
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(CC#N)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a suspension of powdered sodium hydroxide (5.76 g, 144.0 mmol) in anhydrous dimethylsulfoxide (0.14 mL) was added a mixture of 4-methyl-2-nitro-anisole (2.0 mL, 14.4 mmole) and phenylthioacetonitrile (1.88 mL, 14.4 mmole) in anhydrous dimethylsulfoxide (14 mL). The reaction mixture was kept under 30° C. After stirring for one hour at room temperature, the reaction mixture was poured into ice water (400 mL) and 6N hydrochloric acid (40 mL). The mixture was extracted with dichloromethane. The organic layer was washed with water, dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. The resulting solid was washed with a small amount of hexanes and a small amount of ethyl acetate to give (5-methoxy-2-methyl-4-nitro-phenyl)-acetonitrile as a solid (2.40 g, 81%). 1H NMR (CDCl3) δ: 2.32 (s, 3H), 3.73 (s, 2H), 3.99 (s, 3H), 7.15 (s, 1H), 7.73 (s, 1H).
Reaction SMILES: [F:1][CH:2]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[BH4-].[Na+]>CO>[F:1][CH:2]1[CH:8]([OH:9])[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(O)C(F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product from Step B (0.300 g, 1.30 mmol) in MeOH (6 mL) at 0° C. was added NaBH4 (0.123 g, 3.24 mmol) in one portion, and the mixture was warmed to ambient temperature and stirred for 5.0 hours. The mixture was concentrated and the residue was taken up in EtOAc (20 mL) and a saturated aqueous NH4Cl solution (5 mL) and water (5 mL). The layers were mixed and separated and the aqueous phase extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine and dried over Na2SO4, then filtered and concentrated. The crude product was purified by column chromatography (12% to 60% EtOAc/hexanes gradient) to provide 0.130 g (43%) of the major isomer as a colorless oil that solidified overnight to a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=[O:18])[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].[Li][CH3:21]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1([OH:18])[CH3:21])[CH2:15]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C3)C1=O)C2
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CC3CC(CC(C3)C1(C)O)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
At −78° C., to a solution of ketone 20C (500 mg, 1.9 mmol) in 20 mL of THF was added MeLi (1.6 M in ether, 5 mL, 8.0 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes before it was quenched by 5 mL of NH4Cl aq (Sat'd) solution. The mixture was extracted by DCM (5 mL×3) and the combined DCM layers were dried over Na2SO4. Solvent was remove under vacuum and the residue was purified by silica gel chromatography Hexane:EtOAc 1:1(v/v)) to give the title compounds 20D (410 mg, 77%) as a mixture of equatorial and axial isomers. LC-MS (ESR): m/z=282 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([NH:27][C:28](=[O:33])C(Cl)(Cl)Cl)[CH:23]=[CH:22][CH:21]=2>>[NH2:16][C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([NH:27][C:28]([NH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=1)=[O:33])[CH:23]=[CH:22][CH:21]=2
Reactant: Nc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2cn1
Reactant: NCc1ccc(N2CCCCCC2)cc1
Product: Nc1cc2c(NC(=O)NCc3ccc(N4CCCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 1B using 4-(1-azepanyl)benzylamine and the product from Example 150A instead of 2-(3-fluorophenyl)ethylamine and the product from Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.19 (s, 1H), 7.88 (d, 1H, J=8.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.09 (m, 3H), 6.76 (t, 1H, J=5.4 Hz), 6.66 (m, 3H), 5.90 (s, 2H), 4.17 (d, 2H, J=5.4 Hz), 3.24 (m, 4H), 1.71 (m, 4H), 1.44 (m, 4H); MS (ESI) 390 (M+H)+; Anal. Calcd for C23H27N5O.0.4H2O: C, 69.64; H, 7.06; N, 17.65. Found: C, 69.53; H, 6.81; N, 17.38.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[C:11]1([O:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl.CN(C)CCN>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:18]([O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 100 g (596 mmol) of L-valine methyl ester hydrochloride and 84.92 g (542 mmol) of phenylchloroformate in 600 mL of water and 600 mL methylene chloride at 0° C. was added 139.0 g of Na2CO3 (1.311 mol) in portions. After addition was complete the cooling bath was removed and the solution was stirred at ambient temperature for one hour. The organic layer was separated, 1.0 mL of N,N-dimethylethylenediamine (11.0 mmol) was added to the organic layer and the solution mixed for three minutes. The organic layer was washed with 100 mL of 1M potassium hydrogen sulfate solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 135.65 g of the title compound as white crystalline solid; mp 59.1° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25])=[O:10].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25])=[O:10]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](OCC)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Yield: 64.4 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 25, 1.9 g, 4.85 mmol), potassium hydroxide (1.9 g, 34.01 mmol), and hydrazine hydrate (1.71 mL, 34.01 mmol) in ethylene glycol (150 mL) was stirred for 40 h at 120° C. The reaction mixture was poured in to water (120 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo to yield the crude product, which was triturated with water (30 mL) to afford 3,4-dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide 1.0 g (65%) as solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].O/[C:9](/[CH:18]([CH3:20])[CH3:19])=[CH:10]\[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(O)C>[CH:18]([C:9]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(=O)/C=C(\O)C(C)C
Reactant: N=C(N)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)C)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trifluoroethanimidamide (7.08 g, 53.7 mmol, Matrix) in ethanol (85 mL, 1400 mmol) was added ethyl (3Z)-4-hydroxy-5-methyl-2-oxohex-3-enoate (10.00 g, 53.70 mmol, Alfa Aesar). The mixture was then cooled in an ice bath, and a solution of hydrogen chloride in ethanol (84 mL, prepared by bubbling HCl gas through the ethanol for 10 minutes) was added. The reaction was allowed to warm to room temperature and stir overnight. The mixture was added dropwise to a saturated solution of sodium bicarbonate. After complete neutralization was achieved, ethanol was removed in vacuo. The product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes (9.14 g, 65%). 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 4.52 (q, J=7.1 Hz, 2H), 3.22 (hept, J=6.9 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.38 (d, J=6.9 Hz, 6H); LCMS (M+H)+: 263.1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([NH:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)=[CH:32][CH:31]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)(=O)C>CO>[CH:38]1([CH2:37][O:36][C:33]2[CH:34]=[CH:35][C:30]([C:29]([NH:28][C@@H:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=3)[C:14]([NH:13][CH2:12][CH2:11][OH:10])=[O:42])=[O:41])=[CH:31][CH:32]=2)[CH2:40][CH2:39]1
Reactant: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCC2CC2)cc1
Reaction time: 1.5 h
Yield: 54.2 %

Procedure:
Potassium carbonate (32 mg, 0.23 mmol) was added at room temperature to a methanol (230 mL) suspension of 2-({(2S)-2-{[4-(cyclopropylmethoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate (1.17 g, 2.30 mmol) prepared in Example 50. The mixture was stirred for 1.5 hours, and then the reaction solution was evaporated. To the obtained residue was added ethyl acetate (200 mL). The mixture was washed with a saturated ammonium chloride aqueous solution (200 mL) and saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated to give a crude crystalline solid, which was recrystallized with ethyl acetate (20 mL) to give 582 mg of the title compound (white powder, yield: 54%).
Reaction SMILES: COCC(Cl)=O.[O:7]([CH2:14][C:15]([O:17][CH2:18][CH:19]([O:32][CH2:33][N:34]1[CH:42]=[N:41][C:40]2[C:39](=[O:43])[NH:38][C:37]([NH2:44])=[N:36][C:35]1=2)[CH2:20][O:21][C:22](=[O:31])[CH2:23][O:24][C:25]1C=CC=CC=1)=[O:16])[C:8]1C=CC=CC=1>>[CH3:25][O:24][CH2:23][C:22]([O:21][CH2:20][CH:19]([O:32][CH2:33][N:34]1[CH:42]=[N:41][C:40]2[C:39](=[O:43])[NH:38][C:37]([NH2:44])=[N:36][C:35]1=2)[CH2:18][O:17][C:15](=[O:16])[CH2:14][O:7][CH3:8])=[O:31]
Reactant: Nc1nc2c(ncn2COC(COC(=O)COc2ccccc2)COC(=O)COc2ccccc2)c(=O)[nH]1
Agent: COCC(=O)Cl
Product: COCC(=O)OCC(COC(=O)COC)OCn1cnc2c(=O)[nH]c(N)nc21

Procedure:
Reaction of hydrated 9-(1,3-dihydroxy-2-propoxymethyl)guanine (1 mmole) with methoxyacetyl chloride (4 mmole) according to the method used for 9-[1,3-bis(phenoxyacetoxy)-2-propoxymethyl]guanine (Example 14) gives, after chromatography, the desired product. Confirmation of structure and purity are obtained by NMR and TLC (9:1CHCl3 --MeOH).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[CH2:9]([O:11][C:12]#[CH:13])[CH3:10]>C(N(CC)CC)C>[CH2:12]([O:11][C:9]1[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[CH:10]=1)[CH3:13]
Reactant: CCCC(C)C(=O)Cl
Reactant: C#COCC
Solvent: CCN(CC)CC
Product: CCCC1(C)C(=O)C=C1OCC
Yield: 77 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al [J. Org. Chem, 38, 1451–1455, (1973)]; to a solution of 2-methyl pentanoyl chloride (3.91 ml) and ethyl ethynylether (5 g, 40% solution in hexanes, 28.6 mmol) in ET2O (35 ml) at room temperature was added triethylamine (9.9 ml), with stirring. The reaction was warmed to 50° and stirred for 72 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a colourless oil (3.71 g, 17.9 mmol, 77%). δH (CDCl3, 300K), 4.84 (1H, s), 4.24–3.98 (2H, m), 2.04 (3H, s), 1.56–1.43 (4H, m), 1.30–1.26 (3H, m), 0.91 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 178.1 (MH+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=2)=[CH:15][CH:14]=1.O.CCOC(C)=O>N1CCCCC1.[Cu]I>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=3)=[N:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: OCCOc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 253 mg (0.22 mmol) tetrakis-triphenylphosphane-palladium and 42 mg (0.22 mmol) CuI are added to a solution of 2.9 g (11 mmol) 2-(4-iodo-phenoxy)-ethanol and 2.35 g (11 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine in 50 mL piperidine and the reaction mixture is stirred for 30 min at RT. The solvent is eliminated i.vac., the residue is combined with water and stirred with EtOAc. The product precipitated is suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:32]C)[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:32])[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:23]([OH:25])=[O:24])[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CC(=O)OC(C)(C)C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [11-(3-chloro-4-fluorobenzyl)-9-methoxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-decahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetate (50 mg, 0.09 mmol) and 33% hydrogen bromide in acetic acid (1 mL) in dioxane (1 mL) was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([CH3:22])=[C:17](Br)[C:16]=3[O:24][CH3:25])[CH3:14])[N:9]=[C:10]([CH:11]=[O:12])[C:3]=12.[CH3:26][N:27]([CH3:39])[C:28]([C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:24][CH3:25])=[C:17]([C:33]4[CH:32]=[CH:31][C:30]([C:28]([N:27]([CH3:39])[CH3:26])=[O:29])=[N:35][CH:34]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]=[O:12])[C:3]=12
Reactant: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 4-amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde (20 mg, 0.047 mmol), {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (23 mg, 0.12 mmol), sodium carbonate (10 mg, 0.094 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (7.7 mg, 0.0094 mmol) in acetonitrile (0.3 mL)/ethanol (0.1 mL)/water (0.1 mL) was degassed with N2 and then stirred at 95° C. for 3 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by chromatography eluting with CH2Cl2/MeOH (max. MeOH 6%). LCMS calculated for C24H25ClN7O3 (M+H)+: m/z=494.2; Found: 494.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(3-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester (WO2007/97937) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[Cl-].NC(N)=[NH2+].[Na].[CH3:11][C:12]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][CH:23]=[CH:22]2)[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:17][C:13]=1[C:14](Cl)=[O:15].CC1C(=S(=O)=O)C(Br)=C(C)C=C1C(OC)=O.C1CCCC=1>COCCOC>[NH2:3][C:2]([NH2:4])=[N:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])[C:19]([CH:21]2[CH2:25][CH2:24][CH:23]=[CH:22]2)=[CH:20][C:12]=1[CH3:11]
Reactant: Cc1cc(C2C=CCC2)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: C1=CCCC1
Agent: COC(=O)C1=CC(C)=C(Br)C(=S(=O)=O)C1C
Agent: NC(N)=[NH2+]
Solvent: COCCOC
Product: Cc1cc(C2C=CCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A fresh guanidine solution prepared from 5.6 g of guanidinium chloride and 1.6 g of sodium in 40 ml of ethylene glycol dimethyl ether is added to a solution of 1.2 g of 2-methyl-4-(1-cyclopentene-3-yl)-5-methylsulfonylbenzoyl chloride [obtainable by reaction of methyl 2-methyl-4-bromo-5-methyl-sulfonyl-benzoate with cyclopentene in the presence of Pd(II)acetate and tri-o-tolylphosphine, separation of the two isomers by means of a Prebar® stainless steel cartridge 250-50, filled with LiChroprep RP-18; eluent 0.1 m NaH2PO4 buffer/acetonitrile 9:1 with an increasing gradient to 1:1, and subsequent hydrolysis and conversion into the acid chloride with SOCl2 ], in 20 ml of ethylene glycol dimethyl ether with ice-cooling and the mixture is stirred at room temperature for 2 hours. The reaction mixture is then poured onto ice-water, acidified and washed with ethyl acetate and the pH of the solution is adjusted to 10. Customary working-up gives N-diaminomethylene-2-methyl-4-(1-cyclopentene-3-yl)-5-methylsulfonylbenzamide, which can be recrystallized from acetonitrile/diethyl ether, melting point 212°-214°.