Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[S:32][CH:33]=[C:34]([CH3:36])[CH:35]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[S:32][CH:33]=[C:34]([CH3:36])[CH:35]=2)=[C:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=3)[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1
Reactant: Cc1csc(C(=C2CCNCC2)c2ccc(F)cc2)c1
Reactant: O=C(c1cccc(CCl)c1)N1CCCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1csc(C(=C2CCN(Cc3cccc(C(=O)N4CCCCC4)c3)CC2)c2ccc(F)cc2)c1

Procedure:
A solution of this benzoyl piperidine (2.3 9), the above 4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidine (3 g) and triethylamine (3 ml) in toluene was boiled under reflux for 5 h. Water was added to the cooled mixture, the layers were separated and the toluene layer was separated, washed with brine, dried over sodium sulphate and evaporated. The resultant oil (5.6 g) was dissolved in dichloromethane and chromatographed on silica. Elution with dichloromethane/ammonium hydroxide (1%) containing increasing amounts of methanol gave fractions that on evaporation gave the title compound (4.36 g). A solution of this compound in ether was treated with with an ethereal solution of hydrogen chloride. The precipitate was collected and dried to give the hydrochloride salt (3.6 g) m.p. 118-142° C.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][CH2:6][N:5]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@@H:4]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.9 %

Procedure:
To a solution of 77D (1.0 g, 2.7 mmol) in THF (10 mL) at −78° C. was added a solution of LiEt3BH (1.0 M in THF, 13.5 mL, 13.5 mmol, 5 equiv). The mixture was warmed to rt and stirred at rt for 4 h. The mixture was poured over ice and stirred vigorously for 15 min. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 0.5 N HCl (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4) and evaporated to give the crude product as a colorless oil. Purification of the crude product by flash chromatography (5-50% EtOAc/hexane) gave the desired product 77E (960 mg): Rf (50% EtOAc/hexane) 0.64; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.1 min (100%); MS (ES) m/z 346.1 [M+1]+; HRMS calcd for C17H36NO4Si 346.2414, Found 346.2419.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:36]([O:37][CH3:38])=[CH:35][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:36]([O:37][CH3:38])=[CH:35][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])([CH3:34])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(C)(C)O)CC2
Yield: 64 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol. Product isolated as a white foam (68 mg, 64%). MS (ESI+): 527 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 6.65 (s, 1H), 6.57 (d, J=9 Hz, 1H), 6.33 (s, 2H), 5.63 (br s, 1H), 5.32 (br s, 1H), 4.46 (t, 1H), 3.88 (s, 3H), 3.09 (s, 1H), 2.88-2.82 (m, 10H), 2.54-2.49 (m, 3H), 2.28 (d, J=9 Hz, 1H), 1.22 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C@:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Yield: 81.2 %

Procedure:
A mixture of the enantiomer (R)-(−)-5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (3.8 g, 13.3 mmol) and 10% palladium on carbon (48% water wet, 270 g) in methanol (90 ml) was hydrogenated for 1 hour at 50 psi of hydrogen. The catalyst was filtered off through a pad of celite and the solvent was evaporated under reduced pressure; the residue was purified by flash chromatography (eluting with ammoniated chloroform/methanol, 95:5 to 85:15), provided the title compound (2.5 g, 10.8 mmol, 81%): electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[F:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCCCCCC(=O)O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
Lithium hydroxide monohydrate (42.8 mg) was added to a solution of methyl Z-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (190 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (59 mg, yield 32%) as colorless crystals. m.p. 56-57° C.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:49])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:30][CH2:29]4)=[CH:24][C:23]=3[O:38][CH3:39])=[N:19]2)=[C:14]([O:40]COCC[Si](C)(C)C)[CH:13]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[OH:40][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH3:49])[N:20]2[C:15]=1[CH:16]=[N:17][C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:30][CH2:29]3)=[CH:24][C:23]=1[O:38][CH3:39])=[N:19]2
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2c(OCOCC[Si](C)(C)C)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2c(O)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
Into a one dram vial, 2-(4-{4-[7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxy-phenyl}-piperidin-1-yl)-acetamide (89 mg, 0.12 mmol), Methylene chloride (1.50 mL), and Trifluoroacetic Acid (0.50 mL, 6.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The TFA salt was neutralized via a polymer sulfonic acid bound resin and washed with 2M NH3 in methanol. The solvent was removed to afford a yellow solid. The solid was triturated with Et2O to give 2-[4-(4-{5-Hydroxy-7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidin-1-yl]-acetamide as a yellow solid (28 mg, 32%). LCMS (E/I+) 580.15 (M+H). NMR 1H (DMSO-d6)-9.94 (s, 1H), 8.74 (s, 1H), 7.94-8.02 (m 1H), 7.88 (d, 1H, J=8.25 Hz), 7.59-7.67 (m, 1H), 7.48-7.56 (m, 2H), 7.40 (s, 1H), 7.21 (bs, 1H), 7.13 (bs, 1H), 6.85 (s, 1H), 6.67 (d, 1H, J=8.31 Hz), 6.35 (s, 1H), 3.83 (s, 3H), 3.05 (s, 3H), 2.77-2.99 (m, 7H), 2.32-2.45 (m, 1H), 2.06-2.23 (m, 2H), 1.60-1.87 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]O[CH2:38][CH2:37]1.IC(CC)C>CN(C=O)C>[CH3:40][CH:36]([CH2:37][CH3:38])[CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: CCC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(C)C(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
To a cooled (−15° C.) solution of intermediate 23: methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 2-iodobutane (0.068 mL; 0.589 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.039 g (33%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH3:23])[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25]C1C(OC)=C(C(CSC2C=CC=CC=2Br)=CC=1)C(OC)=O>>[Br:24][C:14]1[C:15]([O:22][CH3:23])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[Br:25])(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2ccccc2Br)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2Br)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from methyl 3-bromo-6-(2-bromophenylthiomethyl)-2-methoxybenzoate (Intermediate 81).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[OH:11][CH2:12][CH2:13][CH:14]1[O:18][C:17]2=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:16]2[CH2:15]1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:11][CH2:12][CH2:13][CH:14]2[O:18][C:17]3=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:16]3[CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cn2c(n1)OC(CCO)C2
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)OCCC1Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.4 %

Procedure:
4-Chlorophenylisocyanate (169 ml, 1.1 mmol) and cuprous chloride (50 mg, 0.5 mmol) was added to a solution of 2-hydroxyethyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 31 (0.2 g, 1.0 mmol) in DMF (5 ml) with cooling on ice-bath followed by stirring at room temperature for 4 hours. The mixture was cooled on ice-bath and added 10% hydrochloric acid. The resulting mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-isopropyl ether to afford 2-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl 4-chlorophenylcarbamate (0.16 g, yield 45%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4]([OH:7])(=[O:6])=[O:5].[Na].O.[Cl-].[C:13]1([S+:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[C:26]1([S+:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(O)C(F)(F)CO
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)([O-])C(F)(F)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2 L reactor was charged with 183.7 g (38% purity, 0.38 mole) of sodium 2-hydroxy-1,1-difluoroethanesulfonic acid, 300 mL of water, 450 mL of chloroform and an aqueous solution of triphenylsulfonium chloride [142.8 g (0.49 mole/1.25 equivalents) of triphenylsulfonium chloride and 150 mL of water], followed by stirring at room temperature for 1 hour. A reaction solution was analyzed by using nuclear magnetic resonance (NMR), by which there was found almost half the raw material sodium 2-hydroxy-1,1-difluoroethanesulfonic acid remaining. Accordingly, the reactor was further charged with the aqueous solution of triphenylsulfonium chloride [142.8 g (0.49 mole/1.25 equivalents) of triphenylsulfonium chloride and 150 mL of water], followed by stirring at room temperature for 0.5 hour (triphenylsulfonium chloride was used in an amount of 285.7 g (0.96 mole/2.5 equivalents) in total and the reaction time was 1.5 hours in total). The reaction solution was analyzed by using nuclear magnetic resonance (NMR), by which the raw material was detected being consumed. Thereafter, the reaction solution was separated. The obtained water layer was extracted with 100 mL of chloroform three times while distilling a solvent out of the obtained organic layer, thereby obtaining 328.2 g of the target triphenylsulfonium 2-hydroxy-1,1-difluoroethanesulfonate. In this case, the purity was 48% and the yield was 97%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:22][C:23]([CH3:25])=[O:24]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:22][C:23](=[O:24])[CH3:25])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
In a 250 ml single neck flask was charged 7.5 g (43.1 mmoles,1.0 eq) of m-trifluoromethylbenzaldehyde dissolved in 15 ml of acetone. To this was added 17.2 g of 10% aqueous sodium hydroxide solution (43 mmoles, 1.0 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 9.5 g of 4-(3-trifluoromethylphenyl)-3-buten-2-one as a faintly yellow oil in 88.7% yield.
Reaction SMILES: COC1C=CC2CCCCNC=2C=1.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:25]([CH3:26])=[CH:24][CH2:23][C:22](=O)[NH:21][C:20]=2[CH:28]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:25]([CH3:26])=[CH:24][CH2:23][CH2:22][NH:21][C:20]=2[CH:28]=1
Reactant: COc1ccc2c(c1)NC(=O)CC=C2C
Agent: COc1ccc2c(c1)NCCCC2
Product: COc1ccc2c(c1)NCCC=C2C

Procedure:
The title compound was synthesized following the procedure for synthesizing 8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine using 8-methoxy-5-methyl-1H-benzo[b]azepin-2(3H)-one (Aust. J. Chem. 1978, 31, 2031-2037) as starting material: 1H NMR (DMSO-d6) δ 7.28 (d, 1H), 6.46 (dd, 1H); 6.28 (d, 1H), 5.89 (t, 1H), 5.30 (s, 1H), 3.77 (s, 3H), 3.40 (t, 2H), 2.41 (q, 2H), 2.14 (d, 3H); MS expected 190 (C12H16NO, M+1), found 190.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Product: Nc1ncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (example C.5 step 4) (198 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2 step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (88 mg, 46%). MS (ISP) 387.1 [(M+H)+]; mp 243-246° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=O)[NH:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].B.C1COCC1.Cl>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[CH2:8][NH:10][CH2:11]2)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Yield: 27.7 %

Procedure:
4-Nitrophthalimide (8.0 g, 41.6 mmol) in THF (10 mL) was reduced with BH3-THF (1.0M in THF, 111 mL, 111 mmol) at reflux and treated with 6N HCl to afford 5-nitro-2,3-dihydro-1H-isoindole (1.89 g, 28%) after work-up and purification.
Reaction SMILES: [OH-].[Na+].CO.[CH2:5]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:30][CH2:29][C:28]4[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=4[C:22]3=[O:38])[CH2:17][CH2:16]2)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH3:6].Cl>C(OCC)(=O)C.C1COCC1>[CH2:40]([O:39][C:10]1[CH:11]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:30][CH2:29][C:28]4[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=4[C:22]3=[O:38])[CH2:17][CH2:16]2)[CH:13]=[C:8]([O:7][CH2:5][CH3:6])[C:9]=1[C:42]1[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=1)[CH3:41]
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(OCC)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(OCC)c3)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2,6-diethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (560 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with 6 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (141 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CO)cc3C)cc12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol (from the previous step) in DMSO was added 2-iodoxybenzoic acid (IBX, 2.5 eq). The reaction was stirred at room temperature for 3 hours before being diluted with water. Extraction with EtOAc followed by concentration gave a crude residue which was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzaldehyde.
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19].C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cccc(-c3ccccc3C=O)c2OCC1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.03 g), 2-formylbenzeneboronic acid (0.49 g), tetrakis(triphenylphosphine)palladium(0) (0.35 g), and triethylamine (0.92 ml) in N,N-dimethylformamide (10.3 ml) was stirred at 100° C. under nitrogen atomsphere for 2.5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:30˜1:9) to give a solid of ethyl 2,3-dihydro-9-(2-formylphenyl)-1-benzoxepin-4-carboxylate (0.63 g).