Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]([OH:13])[CH2:11][N:10]([CH3:14])[C:9]2=[O:15])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[OH-].[NH4+].[H][H]>[Pd].C(O)C>[CH3:19][C:16]([C:3]1[CH:4]=[C:5]([N:8]2[CH:12]([OH:13])[CH2:11][N:10]([CH3:14])[C:9]2=[O:15])[N:6]=[N:7][CH:2]=1)([CH3:17])[CH3:18]
Reactant: [H][H]
Reactant: CN1CC(O)N(c2cc(C(C)(C)C)c(Cl)nn2)C1=O
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CN1CC(O)N(c2cc(C(C)(C)C)cnn2)C1=O
Reaction time: 1 h
Yield: 122.4 %

Procedure:
A mixture of 2.0 g (0.00702 mole) of 3-[6-chloro-5-(1,1-dimethylethyl)-3-pyridazinyl]-4-hydroxy-1-methyl-2-imidazolidinone, 2.0 ml of concentrated ammonium hydroxide, 300 milligrams (mg) of 10% palladium on carbon, and 100 ml of 2B ethanol was placed on a Parr shaker apparatus at 50 pounds of hydrogen. After one hour, when the consumption of hydrogen exceeded the theoretical amount, the mixture was filtered and concentrated, giving 2.15 g of a white solid, which was partitioned between 400 ml of methylene chloride and 40 ml of water. The layers were separated and the organic layer was dried with magnesium sulfate.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[S:9](=[O:11])(=[O:10])[NH:8][C:7]2[N:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]1=[O:16])[CH3:3].[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>COCCOCCOC>[CH3:23][N:8]1[C:7]2[N:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5](=[O:16])[N:4]([CH:2]([CH3:1])[CH3:3])[S:9]1(=[O:10])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)N1C(=O)c2cccnc2NS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CC(C)N1C(=O)c2cccnc2N(C)S1(=O)=O

Procedure:
3-(1-Methylethyl)pyrido(2,3-c)(1,2,6)thiadiazin-4(3H)-one-2,2-dioxide (5.0 grams; 0.0208 mole) was mixed with 50 ml of diethylene glycol dimethyl ether. The system was flushed with nitrogen and sodium hydride (1.0 gram; 0.02 mole), previously washed with n-hexane, was added portionwise to the reaction mixture. After the effervescence of hydrogen ceased, 2.2 ml of dimethyl sulfate (0.023 mole, 1.33g/ml) was added and the reaction mixture heated at reflux temperatures for a period of 4 hours. During the reaction, the color of the reaction mixture changed from light yellow to deep red and gradually back to yellow.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl>>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCOCCl
Product: COCCOCOc1cccc(C=O)c1
Yield: 84.6 %

Procedure:
The hydroxyl group of 3-hydroxybenzaldehyde (1.5 g) was protected by use of 2-methoxyethoxymethyl chloride (1.4 g) in accordance with (production process 1), to thereby produce 3-methoxyethoxymethoxybenzaldehyde (2.0 g, yield: 76%). The thus-produced 3-methoxyethoxymethoxybenzaldehyde (1.9 g) and 3,4-dimethoxybenzyl cyanide (1.6 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield a methoxyethoxymethoxy form (hereinafter will be referred to as an “MEM form”) of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.2 g, yield: 48%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1>CCO.Cl.[Pd]>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccccc1OC(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1)C1CNCCO1
Yield: 54.6 %

Procedure:
A solution of 4-benzyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (5 g) in 99% EtOH (150 ml) and HCl (6 ml) was reduced (palladium-charcoal catalyst) for 4 hours at room temperature. The mixture was then filtered, dried under vacuum and separated on a silica gel column (mobile phase: CHCl3 :MeOH:NH4OH=170:30:2) to obtain 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (2.1 g; yield 54.7%) as a transparent oil. HCl m.p. 140°-170° C.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>C(OC(C)C)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: [H][H]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (400 μl). 10% Platinium on carbon (2 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). Spectroscopic data as in Example 40, Method 1.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:31])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[CH:7][CH:6]=1)#[N:2].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC.CO>C1(C)C=CC=CC=1>[F:30][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][C:1]2[N:36]=[N:37][NH:38][N:2]=2)=[CH:6][CH:7]=1)=[O:31]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC#N)c4ccccc34)c2)CC1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCc4nn[nH]n4)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
N-(4-Cyanomethoxynaphthalen-1-yl)-3-fluoro-5-(4-methylpiperidin-1-yl)-benzamide (54 mg, 129 mmol), trimethylsilylazide (0.1 ml, 760 mmol) and dibutyltin oxide (5 mg) are heated to reflux in anhydrous toluene (3 ml) for 5 hours. After cooling to room temperature methanol (5 ml) is then added and the mixture stirred at room temperature for 30 min. The mixture is then evaporated to dryness and the residue recrystallized from ethyl acetate/hexanes to give 3-fluoro-5-(4-methylpiperidin-1-yl)-N-[4-(2H-tetrazol-5-ylmethoxy)-naphthalen-1-yl]-benzamide as a grey powder (22 mg). 1H NMR 300 MHz (DMSO-d6) 10.3 (s, 1H), 8.32 (dd, 1H, J=8.7 and 2.7 Hz), 7.87 (d, 1H, J=9.3 Hz), 7.54-7.62 (m, 2H), 7.42-7.5 (m, 2H), 7.17 (dd, 1H, J=15.9 and 9.3 Hz), 6.97 (d, 1H, J=13.2 Hz), 5.7 (s, 2H), 3.85 (d, 2H, J=19.8 Hz), 2.77 (m, 2H), 1.5-1.78 (m, 3H), 1.25 (m, 2H), 0.95 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([N+:43]([O-])=O)=[CH:5][C:6]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:7]([CH:37]=1)[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]1[C:28]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:27][C:24]([C:25]#[N:26])=[C:23]([N+:34]([O-])=O)[CH:22]=1)#[N:2]>CC(O)=O.CC(O)C.[Fe]>[NH2:43][C:4]1[CH:5]=[C:6]([O:38][CH2:39][CH2:40][O:41][CH3:42])[C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([NH2:34])[C:24]([C:25]#[N:26])=[CH:27][C:28]=2[O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:37][C:3]=1[C:1]#[N:2]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COCCOc1cc(C#N)c(N)cc1OCCOCCOCCOCCOc1cc(C#N)c(N)cc1OCCOC
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of 4-(2-(2-(2-(2-(5-cyano-2-(2-methoxyethoxy)-4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)-2-nitrobenzonitrile (0.2 g) in AcOH (10 mL) and i-PrOH (10 mL) was added iron powder (0.5 g). The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was cooled to room temperature, filtered, the precipitate washed with EA (10 mL). The combined washings and filtrate were concentrated under reduced pressure and purification by silica chromatography to give 0.18 g of 2-amino-5-(2-(2-(2-(2-(5-amino-4-cyano-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)benzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 6.91 (s, 1H), 6.88 (s, 1H), 6.34 (s, 1H), 6.25 (s, 1H), 4.30 (br, 2H), 4.22-4.05 (m, 10H), 3.88-3.65 (m, 16H), 3.43 (s, 6H).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C>[OH:1][CH:2]([CH2:28][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCN(C)CC1
Temperature: 70 °C
Yield: 31.8 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and N-methylpiperazine (200 ul, 1.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was recrystallised from acetonitrile. The solid was filtered, washed with diethyl ether and dried to give 7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (41 mg, 32%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].C([O-])([O-])=O.[K+].[K+].Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:33]=[N:32][N:31]=1>CN(C=O)C>[O:12]1[CH:13]2[C@@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]([C@:18]3([OH:21])[CH2:17][CH2:16][C:14]2=[O:15])[CH2:20][C:7]2=[C:6]4[C:11]1=[C:10]([O:22][C:30]1[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=[N:32][N:31]=1)[CH:9]=[CH:8]2
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(Oc6nnnn6-c6ccccc6)c4OC2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 20 h
Yield: 134 %

Procedure:
A mixture of 2.4 g (79.6 mmol) oxymorphone, 24 g (173.6 mmol) anhydrous K2CO3 and 14.55 g (80.1 mmol) 5-chloro-1-phenyl-1H-tetrazole in 300 ml dry DMF was stirred at room temperature under argon for 20 hours. Then the reaction mixture was filtered, washed with CHCl3 and the filtrate was evaporated in vacuo. The oily residue was dissolved in 200 ml CHCl3, extracted with 1 N NaOH, water and brine. The organic layer was dried and evaporated to give 47.5 g of an oil, which was converted to the oxalate salt to yield 41.5 g (91%) of 4,5-epoxy-14-hydroxy-N-methyl (-3-(1-phenyl-1H-5-tetrazolyloxy) morphinan-6-one.(CO2H)2.2H2O, m.p. 143°-148°. The base was crystallized with ethyl acetate, m.p. 99°-102°, [α]D --179.0° (C 0.83, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1C(=O)N([Cl:23])C(=O)C1>CC#N>[Cl:23][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Solvent: CC#N
Product: COc1cc2c(cc1Cl)CCC(=O)C2(C)C
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3.37 g, 16.5 mmol) was dissolved in CH3CN (82 mL), added with NCS (2.42 g, 1.1 eq.) and stirred at 90° C. for 1.5 hr. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed and the target compound was obtained after concentration under reduced pressure (yellow oily substance, 4.45 g).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([O:55][CH3:56])[C:9]=1/[CH:10]=[CH:11]/[CH:12]([S:22]([CH:25](/[CH:35]=[CH:36]/[C:37]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([O:45][CH3:46])=[CH:39][C:38]=1[O:47][CH3:48])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([NH2:34])[CH:27]=1)(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([NH2:21])[CH:14]=1>>[CH3:56][O:55][C:49]1[CH:50]=[C:51]([O:53][CH3:54])[CH:52]=[C:8]([O:7][CH3:6])[C:9]=1/[CH:10]=[CH:11]/[CH:12]([S:22]([CH:25](/[CH:35]=[CH:36]/[C:37]1[C:38]([O:47][CH3:48])=[CH:39][C:40]([O:45][CH3:46])=[CH:41][C:42]=1[O:43][CH3:44])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([NH:34][C:3]([O:2][CH3:1])=[O:4])[CH:27]=1)(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([NH:21][C:3]([O:2][CH3:1])=[O:4])[CH:14]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COC(=O)Nc1cc(C(/C=C/c2c(OC)cc(OC)cc2OC)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)OC)c2)ccc1OC
Yield: 51 %

Procedure:
A solution of methylchloroformate (10 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by recrystallization from 2-propanol. (yield 51%, m.p. 188-191° C.)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][O:16][CH3:17].[I-].[K+]>C(O)C.O>[CH3:17][O:16][CH2:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COCCBr
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(C(=O)O)cc1

Procedure:
4-Hydroxybenzoic acid (3.00 g, 2.17×10−2 mol) was dissolved in a mixture of ethanol (15 cm3) and potassium hydroxide (3.22 g, 5.64×10−2 mol) in water (5 cm3). The solution was then heated gently and stirred before 1-bromo-2-methoxyethane (3.32 g, 2.39×10−2mol) and potassium iodide (0.01 g, 6.02×10−5 mol) was added slowly. The resulting reaction mixture was then refluxed (15 hrs) and the solvent evaporated and the resulting solid residue dissolved in water (50 cm3). The solution was washed with ether and then made strongly acidic with hydrochloric acid. The resulting precipitate was isolated and recrystallised from ethanol. Yield 1.36 g (32%).
Reaction SMILES: [CH2:1]1[C@H:13]2[C@H:4]([N:5]([CH2:14][CH2:15][NH2:16])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1.C=O.[C:19](O)(C(F)(F)F)=O>CCO>[CH2:14]1[N:5]2[C:6]3[C:11]([CH2:12][C@@H:13]4[CH2:1][CH2:2][CH2:3][C@H:4]42)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:19][NH:16][CH2:15]1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCN1c2ccccc2C[C@H]2CCC[C@H]21
Agent: C=O
Solvent: CCO
Product: c1cc2c3c(c1)C[C@@H]1CCC[C@H]1N3CCNC2

Procedure:
A flask containing Cis 2-(1,2,3,3a,9,9a-Hexahydro-cyclopenta[b]quinolin-4-yl)-ethylamine (0.18 g, 0.84 mmol) and 0.07 ml of 37% aqueous formaldehyde in 2 ml of EtOH was treated with TFA (0.07 mL, 0.92 mmol) at room temperature for 1 hr. The mixture was concentrated under reduced pressure, and the residue was taken up in dichloromethane, washed with 1 N NaOH (15 mL), Brine (15 mL) and then dried with MgSO4. Evaporation and flash chromatography (10% 2N NH3 in ethanol/dichloromethane) afforded the title compound, which was converted to the HCl salt to give a brown solid (0.19 mg, 85%): The same step 5 procedure was used to prepare the trans isomer except that Trans 2-(1,2,3,3a,9,9a-Hexahydro-cyclopenta[b]quinolin-4-yl)-ethylamine was used instead of the cis isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.I[CH:51]([CH3:53])[CH3:52].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:51]([CH3:53])[CH3:52])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(C)I
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A mixture of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (4 g, 5.95 mmol), 2-iodopropane (6 g, 35.72 mmol) and K2CO3 (2.5 g, 17.86 mmol) in CH3CN (50 mL) was stirred at reflux for 2 days. The mixture was cooled to rt, filtered and the filtered cake was washed with CH3CN (20 mL). The filtrate was concentrated and the residue was purified by Combi-Flash (80 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:1 by gradient, 60 mL/min, 40 min, 2.4 L total solvent volume) to afford the desired compound (3 g, yield: 71%) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.15 (s, 1H), 7.38-7.29 (m, 5H), 7.19 (d, J=4.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 6.41 (dd, J=8.5 and 2.0 Hz, 1H), 6.20 (d, J=2.5 Hz, 1H), 5.36-5.32 (m, 1H), 5.09 (s, 1H), 5.07 (s, 1H), 4.94-4.89 (m, 3H), 4.65 (s, 2H), 4.17-4.14 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.41-3.35 (m, 0.5H), 3.04-2.95 (m, 0.5H), 2.94-2.86 (m, 1H), 2.72-2.52 (m, 2H), 2.25 (t, J=7.5 Hz, 1H), 2.21 (t, J=8.0 Hz, 1H), 2.05-1.90 (m, 2H), 1.90-1.82 (m, 0.5H), 1.76-1.70 (m, 0.5H), 1.65-1.55 (m, 5H), 1.42-1.34 (m, 4H), 0.95 (d, J=6.5 Hz, 3H), 0.83-0.80 (m, 3H) ppm; ESI-MS (m/z): 714.4 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:35])[C@@H:9]([NH:18][C:19]([C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.[CH3:36][N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42](B(O)O)[CH:43]=2)[C:38]1=[O:49]>O.C(#N)C>[NH2:7][C:8](=[O:35])[C@@H:9]([NH:18][C:19]([C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:49])[N:37]([CH3:36])[CH2:45]3)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CN1Cc2cc(B(O)O)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)ccc2C1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Potassium carbonate (276 mg) in water (2.0 mL) was added to (S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 517 mg), 2-methyl-1-oxoisoindolin-5-ylboronic acid (Example 31, step (iii), 191 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (98 mg) in degassed acetonitrile (12 mL) at 20° C. under nitrogen. The resulting solution was stirred at 80° C. for 30 min. The reaction mixture was cooled, filtered and diluted with dichloromethane, and washed with water. The organic extract was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography in silica eluting with methanol/ethyl acetate (5:95 to 15:85). Pure fractions were evaporated to dryness to afford the sub-titled compound (469 mg).
Reaction SMILES: C(NCC)C.C([Li])CCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].[O:25]1[CH2:29]C[CH2:27][CH2:26]1>>[CH2:11]([Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[C:27]#[C:26][O:25][CH3:29])[CH2:12][CH2:13][CH3:14]
Reactant: C1CCOC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCNCC
Product: CCCC[Sn](C#COC)(CCCC)CCCC
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of freshly distilled diethylamine (9.6 mL, 92 mmol, 3.9 equiv) in tetrahydrofuran (300 mL) at 0° C. was added n-butyllithium (2.5 M in hexanes, 32 mL, 80 mmol, 3.4 equiv). After stirring for 10 min, 1,1-dimethoxy-2-chloro-acetaldehyde (4.0 mL, 26 mmol, 1.1 equiv) was added dropwise to the reaction mixture. The reaction was stirred for 2 hours at 0° C. Tributyltin chloride (6.2 mL, 24 mmol, 1.0 equiv) was then added to the reaction mixture. The reaction was warmed to 23° C. over 1 hour and stirred for 8 hours. The volatiles were removed in vacuo and the reaction mixture was re-suspended in hexane (30 mL) and filtered through a glass frit under an argon atmosphere. The solution was then re-concentrated by rotary evaporation and distilled by Kugelrohr to yield 6.4 g (78%) of 10 as a colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:16][O:17][CH2:18][CH2:19][CH3:20]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:15]([CH3:14])[CH2:16][O:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCOCC(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Product: CCCOCC(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 35.4 %

Procedure:
Procedures similar to those in Preparation Example 8 were carried out by using 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.1 g of 4-(1-methyl-2-propoxyethoxy)-benzyl bromide to obtain 1.43 g of the aimed compound as an oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[P:5]([CH:10]([CH3:18])[CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[OH-].[NH4+:23]>C(O)C>[NH2:23][C:12](=[O:13])[CH:11]([F:17])[CH:10]([P:5]([CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9])[CH3:18]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)C(C)P(=O)(OCC)C(OCC)OCC
Agent: [OH-]
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)C(F)C(N)=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluorobutanoate (1.8 g, 5.5 mmol) in ethanol (3 mL) was added concentrated ammonium hydroxide (14.8 M, 0.5 mL, 7.4 mmol). The solution was stirred for 24 h at 40° C. and then evaporated to give 1.6 g (97%) of a diastereomeric mixture of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxymethyl)phosphinate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 5.7–6.7 (m, 2H), 4.9–5.5.6 (m, 1H), 4.7–4.8 (m, 1H), 4.1–4.4 (m, 2H), 3.8–4.0 (m, 4H), 2.8–3.0 (m, 1H), 1.2–1.4 (m, 12H).