Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].I.[CH:12](=O)[CH2:13][CH3:14].CC1NC(C(OCC)=O)=C(C)C=1C>CCOCC.C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:12][CH2:13][CH3:14])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CCC=O
Agent: CCOC(=O)c1[nH]c(C)c(C)c1C
Agent: I
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCc1[nH]c(C)c(C(C)=O)c1C
Yield: 59 %

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (1.02 g), acetic acid (15 ml), aqueous hydriodic acid (25ml) and propionaldehyde (1.74g), were stirred at 25° C. three hours under nitrogen. The work up was the same as that of 2,3,4-trimethyl-5-carbethoxy-pyrrole in Example 4 except that 2 × 50 ml ether were used. Recrystallization from benzene gave the product 0.786 g (59%) m.p. 157°-158°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:14]([C:15]([NH2:17])=[O:16])=[C:7]1[NH:6][C:5]2=[O:31].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[C:13]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[C:14]([C:15]([NH2:17])=[O:16])=[C:7]1[NH:6][C:5]2=[O:31])(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1cc(N)ccc12
Product: C=CC(=O)Nc1ccc2c(c1)c(=O)[nH]c1c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn12

Procedure:
Compound 78 was prepared from 7-amino-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide and acryloyl chloride according to the procedure similar to that for compound 8. 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.77 (s, 1H), 8.65 (s, 1H), 8.24 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.48-7.52 (m, 2H), 7.2-7.15 (m, 5H), 6.57 (dd, J=9.2, 18.0 Hz, 1H), 6.37 (d, J=18.0 Hz, 1H), 5.87 (d, J=9.2 Hz, 1H). MS (ESI, m/e) [M+1]+ 466.1.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.O.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>CCOCC.CCCCCC>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][CH:10]1[S:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: CN(C)CCCl
Reactant: c1ccc2c(c1)CSc1ccccc1S2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CN(C)CCC1Sc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.40 g of 11H-dibenzo(b,e)-1,4-dithiepin (K. Sindelar, M. Protiva and M. Hrubantova, Czech. 202.239) in 50 ml of ether was treated dropwise over 20 minutes of 15% n-butyllithium solution in hexane in a nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature and then treated with external cooling with ice and water and with 10 ml of 2-dimethylaminoethyl chloride, added dropwise. Then, the mixture was stirred for another 2 hours at room temperature. It was then washed with water and the basic product extracted into a mild excess of 1:1 dilute hydrochloric acid. The acid aqueous layer was separated, made alkaline with aqueous ammonia and the base extracted with ether. The extract was dried with potassium carbonate and evaporated. The remaining oily base was dissolved in 7 ml of acetone and treated with a solution of 1.81 g of oxalic acid in 5 ml of acetone. The crystalline hydrogen oxalate (5.31 g) separated, was filtered with suction and purified by recrystallization from aqueous ethanol, m.p. 195°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC[C@@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 mL) and formaldehyde (2.4 mL, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH was monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with 6 N NaOH, 1 N NaOH, and 2 N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×). The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]#[N:24])=[O:17].C(N(CC)CC)C>ClCCl>[OH:13][CH:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][NH:2][CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]#[N:24])=[O:17]
Reactant: NCC(O)COc1ccccc1
Reactant: N#CC1CCCN1C(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1CCCN1C(=O)CNCC(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A solution of 1-amino-3-phenoxypropan-2-ol hydrochloride (7.9 g, 38.8 mmol) and 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (6.1 g, 35.3 mmol) in DCM (250 mL) was added triethylamine (15 mL, 106 mmol). The mixture was stirred at room temperature overnight. After the TLC showed that the reaction was complete, the mixture was washed by brine. The aqueous solution was extracted with dichloromethane (DCM) (3×100 mL) and the combined DCM solution was concentrated to give a crude product, which was purified by column chromatography to give 3.5 g of 1-(2-(2-hydroxy-3-phenoxypropylamino)acetyl)pyrrolidine-2-carbonitrile (as shown at 6). Yield was 33.6%.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Mg].C1C2C(=CC=CC=2)C=C1.Br[Mg].[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[B:32]([N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])Cl>O1CCCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[B:32]([C:24]1[CH2:25][C:26]2[C:31]([CH:23]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:36])[CH3:37]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)N(B(Cl)C1=Cc2ccccc2C1)C(C)C
Agent: C1=Cc2ccccc2C1
Agent: [Mg]
Agent: [Mg]Br
Solvent: C1CCOC1
Product: CC(C)N(B(C1=Cc2ccccc2C1)C1=Cc2ccccc2C1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 121 %

Procedure:
In a stream of nitrogen, 3.1 g (15.9 mmol) of 2-bromoindene and 1.6 g of magnesium were caused to react with each other in 50 ml of tetrahydrofuran, whereby a reaction solution containing bromomagnesium indene was obtained. The reaction solution was added dropwise to a solution prepared by dissolving 4.11 g (15.7 mmol) of (2-indenyl)(diisopropylamino)chloroborane synthesized in the above section (1) in 30 ml of tetrahydrofuran at 0° C. After the mixture had been stirred at room temperature for 4 hours, the solvent was removed by distillation, and the remainder was extracted twice with 40 ml of hexane and 10 ml of dichloromethane, whereby 6.47 g (19.0 mmol) of bis(2-indenyl)(diisopropylamino)borane as a pale yellow solid were obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[O:5].C(OC([NH:40][C:41](=NC(=O)OC(C)(C)C)[N:42]1C=CC=N1)=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[O:5])[C:41]([NH2:42])=[NH:40]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CNC
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CN(C)C(=N)N
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(Methylamino)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide (416 mg, 1.2 mmol) was taken up in 10 mL of DMF along with tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (154 mg, 1.2 mmol) and DIEA (154 mg, 1.2 mmol). The resulting reaction mixture was stirred at room temperature for 24 h. It was then diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (pentane/EtOAc) afforded 350 mg of the di-Boc derivative of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(1-methylguanidino)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide (43% yield). MS (EI) calcd for C32H51N3O4 541.39. found 542 [M+H]+.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH:8]=[C:9]([C:14]1[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:16]=3[CH:15]=1)[CH2:10]2)=O)C.O.NN.[OH-].[K+].O>C(O)CO>[CH3:24][O:23][C:22]1[C:16]2[CH:15]=[C:14]([C:9]3[CH2:10][CH:11]4[NH:6][CH:7]([CH2:13][CH2:12]4)[CH:8]=3)[S:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)N1C2C=C(c3cc4c(OC)cccc4s3)CC1CC2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1cccc2sc(C3=CC4CCC(C3)N4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of (±)-8-ethoxycarbonyl-3-(4-methoxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-ene (0.719 g, 2.09 mmol), hydrazine hydrate (0.51 mL, 10.4 mmol) and KOH (0.700 g, 12.5 mmol) in ethylene glycol (15 mL) was heated at reflux in a sand bath for 3 h. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was poured into water (20 mL). This mixture was extracted with Et2O (3×30 mL). The combined organic layers were washed with 1.0 N HCl (1×175 mL). The layers were separated and the aqueous layer was basified with 2.5 N NaOH (25 mL). This layer was extracted with EtOAc (2×275 mL). The combined organic layers were then dried over MgSO4, concentrated, and the residue was purified by medium pressure chromatography (silica gel, 7% (10% conc. NH4OH in MeOH)/CH2Cl2] to give the intermediate title compound as an orange semi-solid (0.574 g, quantitative yield). mp (oxalate) 204-207° C. IR (KBr) 3400 (br) cm−1. Ion Spray MS 272 (M+H)+; 255 (M-16)+(base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(Cl)cc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(CC(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 29.7 %

Procedure:
The acid from Step 1 (9.01 g, 29.6 mmol) and triethylamine (3.03 g, 29.9 mmol) were dissolved in 45 mL of anhydrous toluene, cooled to 0° C. and treated with diphenylphosphoryl azide (8.22 g, 29.9 mmol). The solution was maintained at 0° C. for 10 minutes and warmed to room temperature for 2 hours. The reaction was poured into water, extracted with ether, dried over anhydrous MgSO4, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to 90° C. for 15 minutes. Tert-Butyl alcohol (10 mL) was added to the reaction mixture. After an additional twenty minutes, concentrated hydrochloric acid (8 mL) was cautiously added and the reaction maintained at 90° C. for 15 minutes. The solution was cooled to room temperature and a precipitate formed that was isolated by filtration, washed with ether and air dried to provide the desired ketone as a white solid (2.43 g, 30%): mp 143°-147.5° C. 1H NMR (CDCl3) 300 MHz 8.08 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.24 (m, 4H), 4.35 (s, 2H), 2.05 (s, 3H). Mass spectrum: M+H=277.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]2([NH2:16])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:17][CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[C:7]1([C:13]2([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[Br:17])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(Br)C(=O)Cl
Reactant: NC1(c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(Br)C(=O)NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-phenylcyclopropylamine (8.9 g) and triethylamine (7.4 g), and α-bromo-tert-butylacetyl chloride (14.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 14.8 g of N-(1-phenylcyclopropyl)-α-bromo-tert-butylacetamide. M.P., 161°-162.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1.C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[CH:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:12]
Reactant: O=Cc1cccs1
Reactant: COc1cccc2c1CCC2=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cccc2c1CC(=Cc1cccs1)C2=O
Temperature: 130 °C
Yield: 88.1 %

Procedure:
To 4-methoxy-1-indanone (0.1 g; 0.62 mmol) were added thiophene-2-carboxaldehyde (87.5 μl ; 0.93 mmol), piperidine (18.5 μl ; 0.18 mmol) and acetic acid (10.7 μl ; 0.18 mmol). After heating at 130° C. for 90 minutes the mixture was taken up in CH2Cl2, washed with water and purified by flash chromatography, eluting with petroleum ether/ethyl acetate (95/5) to give 4-methoxy-2-(2-thienylmethylene)-1-indanone (140 mg; 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:45][C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Nc1ccncc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccncc4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and Pyridin-4-ylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-pyridin-4-yl-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (30 mg, 61%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.27 (m, 1 H) 6.78 (m, 2 H) 6.94 (m, 3 H) 7.81 (d, J=8.46 Hz, 1 H) 8.01 (dd, J=8.64, 2.02 Hz, 1 H) 8.22 (m, 3 H) 8.72 (d, J=6.99 Hz, 2 H) 8.83 (s, 1 H) 8.96 (d, J=8.46 Hz, 1 H) 9.50 (s, 1 H) 11.10 (s, 1 H) 11.35 (s, 1 H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: C([SiH](CC)CC)C.O[CH:9]([C:16]1[S:30][C:19]2[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N:21][N:22]([CH3:25])[C:23](=[O:24])[C:18]=2[CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH3:25][N:22]1[C:23](=[O:24])[C:18]2[CH:17]=[C:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:30][C:19]=2[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N:21]1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3ccccc3)sc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1nn(C)c(=O)c2cc(Cc3ccccc3)sc12
Reaction time: 24 h
Yield: 81 %

Procedure:
Triethylsilane (1.0 ml) was added to a stirred solution of 2-[1-hydroxy-1-phenylmethyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (example 14, 1.44 g) in trifluoroacetic acid (2 ml) and dichloromethane (10 ml) at room temperature. After 24 hours, saturated sodium hydrogen carbonate solution (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The organic extracts were washed twice with saturated sodium hydrogen carbonate solution, then with brine, and then dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:4 then 1:3), to give the title compound (1.11 g) as a solid.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:29])=[CH:22][CH:23]=4)[C:18](=O)[C:17]=3[CH:16]=2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.[Pd]>[ClH:1].[ClH:1].[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[O:29])=[CH:22][CH:23]=4)[CH2:18][C:17]=3[CH:16]=2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C(OCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)OCCCN3CCCCC3)ccc1-2

Procedure:
A solution of 20.0 g (0.04 mole) of bis(3-piperidinopropyl)-9-oxofluorene-2,7-dicarboxylate dihydrochloride in water to make a total volume of 240 ml is hydrogenated over 8.0 g of 10% palladium on charcoal for 2 days at 53°C on a Parr hydrogenation apparatus. The mixture is decanted from the catalyst, filtered through filter aid, treated with charcoal and refiltered. The solution is made basic to phenolphthalein with 20% sodium hydroxide and is extracted three times with CHCl3. The combined extracts are washed twice with water, dried over anhydrous sodium sulfate and filtered. The filtrate is made acidic to Congo Red with ethereal HCl. Most of the solvent is removed on a steam bath under vacuum, and the resulting solid is recrystallized from methanol-ether and from absolute ethanol and vacuum dried to give bis(3-piperidinopropyl)fluorene-2,7-dicarboxylate dihydrochloride.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1.C(O)(=O)C.[BH4-].[Na+]>O>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccnc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(OCc2ccc(CC[N+](=O)[O-])cc2)c1
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
To a dimethyl sulfoxide (50 mL) solution of 4-methyl-2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (3.10 g, 11.5 mmol) described in Manufacturing Example 43-1-3 and acetic acid (3.10 mL) was added sodium borohydride (733 mg, 18.4 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes. Water was then added dropwise into the reaction solution at room temperature while cooling appropriately, and the reaction mixture was 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 (ethyl acetate:heptane=1:5→1:2) to obtain the title compound (1.10 g, 35.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3[C:33]4([C:41]5[C:36](=CC=[CH:39][CH:40]=5)[NH:35][C:34]4=O)COC3=CC=2ON=1.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:33][C:41]1[CH:36]=[N:35][CH:34]=[CH:39][CH:40]=1)[C:10]3=[O:18]
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(Cc2cccnc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (63%) as a colorless solid: mp 164-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.55 (d, J=3.9 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.33-7.13 (m, 3H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.61-6.51 (m, 2H), 6.37 (dd, J=8.4, 2.1 Hz, 1H), 5.08 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.7, 162.1, 161.6, 149.3, 148.8, 141.5, 135.2, 132.4, 131.5, 128.8, 124.0, 123.8, 123.7, 123.4, 120.5, 108.8, 107.5, 96.6, 80.4, 57.5, 55.5, 41.6; MS (ES+) m/z 359.4 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[CH:6]=[CH2:7].[OH-].[Na+].[ClH:20]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([Cl:20])=[O:12])[CH:6]=[CH2:7]
Reactant: C=CCOc1ccccc1C(=O)O
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 2000 ml four-necked reaction flask, equipped with a magnetic stirrer, thermometer, addition funnel, condenser and a nitrogen sweep, was added 281 grams of thionyl chloride (2.38 moles), 1 ml of dimethyl formamide, and 1000 ml of toluene. 356 grams of the allyloxybenzoic acid (2.0 moles) as prepared above was added over approximately 20 minutes. The reaction temperature was kept below 20° C. with an ice/water bath. The nitrogen sweep was connected to a trap, which contained 1000 ml of a 4 M aq. NaOH solution to react with SO2 and HCl that are formed during the reaction. After the addition was complete, the solution was stirred for 3 hours at room temperature and then heated to reflux. After 3.5 hours of reflux, it was cooled to room temperature. Solvent was distilled at atmospheric pressure because removal under reduced pressure caused severe bumping. After most of the solvent was removed, the residue was transferred to a 1000 ml flask equipped with a distillation head. The product was then vacuum distilled.