Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[C:56](Cl)(=[O:58])[CH3:57]>>[C:56]([N:26]1[C@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=3[CH3:21])=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:55])=[O:24])[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27]1)(=[O:58])[CH3:57]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: CC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was acylated with acetyl chloride according to General Procedure F. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 781.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1cncc(Br)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cncc(OC2CCOCC2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromopyridin-3-ol (146 g, 834 mmol), tetrahydro-2H-pyran-4-ol (128 g, 1250 mmol), and triphenylphosphine (329 g, 1250 mmol) in toluene (2.0 L) was heated to reflux, and 750 mL of distillate was removed via a Dean-Stark trap. The reaction mixture was cooled to 60° C., and 547 g (1.25 mol) of a 40% (w/w) solution of DEAD in toluene was added drop-wise over a 1 hour period. The addition was exothermic with the reactor temperature at the end of addition near 95° C. The reaction mixture was stirred at 115° C. for 18 h, and a portion of the reaction solution was sampled and analyzed by HPLC to establish that the reaction was complete. Upon completion of reaction, 500 mL of solvent was removed by distillation, and the pot residue was cooled to ambient temperature. This organic layer was washed with 10% aqueous sodium hydroxide (2×0.50 L) and concentrated under vacuum to produce a viscous oil, which was dissolved in 2N hydrochloric acid (1.0 L). Diatomaceous earth (100 g) was added with stirring and the resulting suspension was filtered. The pad was rinsed with 2N hydrochloric acid (1.0 L), and the filtrates were combined and extracted with diisopropyl ether (500 mL). The diisopropyl ether layer was discarded, and the aqueous layer was treated with carbon black (10 g) and stirred at 45-50° C. for 1 h. The suspension was filtered through a pad of diatomaceous earth (25 g). The filtrate was collected, cooled to 5° C., and the pH adjusted with 50% aqueous sodium hydroxide (250 mL) to pH=13. The solution was extracted twice with chloroform (1.0 L, 600 mL), and the chloroform extracts were combined and concentrated under vacuum to give 12 as a dark red viscous oil/low melting solid (187 g, 87%), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 8.24 (s, 1H), 7.38 (s, 1H), 4.52 (m, 1H), 3.98 (m, 2H), 3.60 (m, 2H), 2.05 (m, 2H), 1.81 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:60])=[C:44]([CH:59]=1)[O:45][CH2:46][CH2:47][O:48][Si:49]([CH:56]([CH3:58])[CH3:57])([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH3:60])=[C:44]([O:45][CH2:46][CH2:47][O:48][Si:49]([CH:53]([CH3:55])[CH3:54])([CH:56]([CH3:58])[CH3:57])[CH:50]([CH3:51])[CH3:52])[CH:59]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(CCl)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(OCCO[Si](C(C)C)(C(C)C)C(C)C)c2)cc1

Procedure:
Analogously to Method D, 0.700 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and [2-(5-chloromethyl-2-methylphenoxy)ethoxy]triisopropylsilane are reacted. The title compound is obtained as a colourless oil. Rf=0.41 (1:2 EtOAc-heptane); Rt=7.94.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[O:12][P:13]1(=O)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([P:13]2(=[O:12])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COP1(=O)Oc2ccccc2-c2ccccc21
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)cc1
Temperature: 110 °C

Procedure:
30.8 g (0.2 mol) of 4-methylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 46 g (0.2 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin 6-oxide were added dropwise over the course of 1 hour while stirring. The temperature was then slowly increased to 110° C. When the reaction was complete, the residue slowly crystallized out at room temperature. 60 g (90% of theory) of the abovementioned compound, which, after recrystallization from toluene, had a melting point of 124 to 125% C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][S:16][CH3:17])[CH:12]=[CH:11][C:10]=1[N+:18]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][S:16][CH3:17])[CH:12]=[CH:11][C:10]=1[NH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CSCc1ccc(N)c(OCc2ccccc2)c1

Procedure:
To a stirred solution of 2-benzyloxy-4-methylsulfanylmethyl-1-nitrobenzene (900 mg, 3.11 mmol) EtOH (80 mL) is added SnCl2 (3.53 g, 18.7 mmol) and the solution is refluxed for 2 h. After the mixture cools to RT the EtOH is removed under reduced pressure and EtOAc is added. The solution is washed with 1N NaOH, water, brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (5:1) as eluent to give the title compound as a yellow liquid. NMR (CDCl3): 7.44-7.31 (m, 5H), 6.85 (d, J=1.77 Hz, 1H), 6.72-6.70 (dd, J=1.77 Hz, 7.83 Hz, 1H), 6.66-6.64 (d, J=7.84 Hz, 1H), 5.08 (s, 2H), 3.59 (s, 2H), 1.95 (s, 3H): (M+1)+=260.
Reaction SMILES: [F:1][C:2]([F:26])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4].CCO.[OH-].[Na+]>C1COCC1>[F:26][C:2]([F:1])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:17])([F:18])[F:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Reaction time: 16 h

Procedure:
To a stirred solution of the ethyl ester (Step 1) (0.090 g, 0.231 mmol) in THF:EtOH:H20(7:2:1) (4 mL) was added aqueous NaOH solution (0.11 mL, 2.5 M). After stirring 16 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H2O, and washed with diethyl ether. The resulting aqueous phase was acidified with concentrated HCl, extracted with diethyl ether, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was purified by flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5% acetic acid). This procedure yielded the title acid (0.020 g, 24%) as a white powder: mp 162.3–164.7° C. 1H NMR (acetone-d6/300 MHz) 8.05 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=8.7 Hz), 5.97 (q, 1H, J=6.8 Hz). FABLRMS m/z 361 (M−H). ESHRMS m/z 361.0111 (M−H, Calc'd 361.0094).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[CH3:8].O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=1
Reactant: C=C(C)C=O
Reactant: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C
Product: Cc1cc(-c2ccc(C)c(C)c2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-dimethylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly brown amorphous powder (yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:16][OH:17])[C:6](=[O:11])[C:5]2([CH3:13])[CH3:12]
Reactant: ClCCOC1CCCCO1
Reactant: CC1(C)C(=O)Nc2ccc(Cl)cc21
Product: CC1(C)C(=O)N(CCO)c2ccc(Cl)cc21

Procedure:
Prepared from 5-chloro-3,3,dimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol.4, page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1>CC(O)C.Br.C(O)(=O)C>[NH2:30][CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:13]2[N:12]([CH2:11][O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Agent: Br
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NCCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Yield: 18.7 %

Procedure:
A mixture of compound (7) (0.0026 mol) in 2-propanol (30 ml) and HBr/acetic acid (2 ml) was stirred and refluxed for 90 minutes and then cooled. The solvent was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried. This fraction was purified again by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried, yielding 0.23 g of (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine (compound 9).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 50 °C

Procedure:
The title compound was prepared by adding the 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (15.20 g, 49.65 mmol), ethanol (130 mL), 30% hydrogen peroxide (aqueous) (130 mL), and 6 N sodium hydroxide (aqueous) (9 mL) to a 2 liter round bottom flask. This mixture was heated at 50° C. for 1 hour, and removed from the heat to allow to cool to room temperature. The pH was adjusted to ˜3 by adding 6 N hydrochloride solution (aqueous) resulting in a precipitate. This precipitate was filtered and washed with water (15.13 g, 94%): ES-MS (m/z) 324 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[H-].[Na+].[F:11][C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[C:14](OCC)=[O:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:19][C:13]([F:20])([C:12]([F:22])([F:21])[F:11])[C:14](=[O:15])[CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)c1cccs1
Reaction time: 0.25 h

Procedure:
2-Acetylthiophene (4.3 ml) was dissolved in dry toluene (40 ml). Sodium hydride (60%, 3.2 g) was added slowly and the mixture was stirred for 15 minutes. Ethyl pentafluoropropionate (13.44 g) was added and the stirring was continued overnight. Sulfuric acid (10%, 50 ml) was added and the phases were separated. The organic phase was washed with water (50 ml) and it was evaporated to dryness. The residue was distilled (b.p. 92–94° C./0.15 mbar) to give the product (9.0 g). 1H NMR (CDCl3): 6.50 (s, 1 H); 7.21 (dd, 1 H, J=3.9 & 4.9); 7.77 (dd, 1 H, J=1.1 & 4.9 Hz); 7.85 (dd, 1 H, J=1.1 & 3.9 Hz). IR (film): 1592 (C═O); 1202 (C—F).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)(=[O:18])=[O:17])[CH2:14][CH2:13][N:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:23]2[CH:24]=[C:19]([S:16]([N:15]3[CH2:14][CH2:13][N:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:10]3[CH3:9])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(-c2ccnc(Cl)n2)c1
Yield: 90 %

Procedure:
2,4-dichloropyrimidine and (S)-tert-butyl 3-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine-1-carboxylate was coupled following procedure A. The yield was 90%. LC-MS showed the product was >95% pure and had the expected M+H+ of 453.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][O:12][CH2:13][CH2:14]O>[Ni].C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: COCCO
Agent: [Ni]
Solvent: C1CCOC1
Product: COCCC1C(=O)Nc2ccccc21

Procedure:
2.0 g (15 mmol) indolin-2-one, 5 mL (63 mmol) 2-methoxyethanol and 1.5 g Raney nickel in 20 mL THF were stirred for 4 h at 200° C. in an autoclave. After the catalyst had been filtered off the mother liquor was evaporated down, the residue was triturated with diisopropylether, suction filtered and dried
Reaction SMILES: [O:1]1[C:7]2([CH3:8])[CH:2]1[C:3]([O:5][C:6]2([CH3:10])[CH3:9])=[O:4].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([O:1][C:7]1([CH3:8])[C:6]([CH3:9])([CH3:10])[O:5][C:3](=[O:4])[CH2:2]1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: CC1(C)OC(=O)C2OC21C
Product: C=CC(=O)OC1(C)CC(=O)OC1(C)C
Yield: 85 %

Procedure:
The obtained 3-hydroxy-3,4,4-trimethyl-γ-butyrolactone was allowed to react with acrylyl chloride in the same manner as in Production Example 16 to thereby yield the title compound (yield: 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B.[Na]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Agent: B
Agent: [Na]
Solvent: CO
Product: CCCC(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
10-bromo-2-(2-oxopentyloxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 40 was suspended in anhydrous methanol (20 ml), and to the suspension was added in small portions sodium boron hydride (92 mg) in an ice bath, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was extracted by adding water and methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 4% methanol) to obtain the title compound (140 mg; 28%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OC)[CH:11]=[CH:10][C:9]=1[CH2:16][C:17](=O)[CH2:18][CH3:19])(C)(C)C.[C:22](O)(C(F)(F)F)=[O:23]>C1COCC1>[CH2:18]([C:17]1[NH:7][C:8]2[C:9]([CH:16]=1)=[C:10]([O:23][CH3:22])[CH:11]=[CH:12][CH:13]=2)[CH3:19]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(=O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCc1cc2c(OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of [5-methoxy-2-(2-oxo-butyl)-phenyl]-carbamic acid t-butyl ester 73b (1.36 g, 4.65 mmole) in 10 ml THF was added 4 ml TFA. The reaction mixture was stirred at room temperature for 5 h, quenched with 50 ml H2O and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10–15% EtOAc in hexane) to give pale yellow solid (1.36 g, 73%). 1H NMR (CDCl3) δ 7.75 (1H, bs), 7.49 (1H, d, J=8.6 Hz), 6.81 (1H, s), 6.73 (1H, d, J=8.6 Hz), 3.83 (3H, s), 2.75 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz). ESIMS (MH+): 272.10.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15]([C:22]4[CH:21]=[CH:20][C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=4)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc2ncnc(N3CCOCC3)c2n1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Clc1ccc(-c2ccc3ncnc(N4CCOCC4)c3n2)cc1Cl
Yield: 97 %

Procedure:
The reaction of 4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine and 3,4-dichlorophenylboronic acid afforded the pure title compound (yield 97%) as a yellowish solid which was characterized by its mass spectrum as follows: MS (m/z): 361.2 ([M+H]+, 100).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([OH:3])[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[CH3:12]
Reactant: COc1cc(OC=O)cc(OC)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a solution of 3,5-dimethoxy-4-methylphenyl formate (2.9 g, 14.8 mmol) in wet MeOH (81 mL) was added K2CO3 (8.1 g, 58.6 mmol). The mixture was stirred for 2 hrs at room temperature then H2O (2-3 mL) was added. After stirring for 21 hrs, the mixture was diluted with H2O, acidified with 6M HCl to pH 3-4, and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-35% EtOAc-hexanes) gave 3,5-dimethoxy-4-methylphenol as an impure yellow powder (0.71 g, 29% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(C(F)(F)F)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-trifluoromethylacetophenone (M. Kihara, M. Kashimoto, and Y. Kobayashi, Tetrahedron, 1992, 48, 67-78). 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.03 (1H, br s), 7.89 (1H, br d, J=7.7 Hz), 7.74 (1H, br d, J=8.1 Hz), 7.59-7.54 (2H, m), 7.33 (1H, dd, J=1.8, 8.4 Hz), 5.93 (2H, br s), 3.80 (2H, q, J=7.0 Hz), 0.88 (3H, t, J=7.0 Hz)
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].Br[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[N:4]1([CH2:3][CH:2]([O:1][CH2:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CCCCCOCC(O)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[2-hydroxy-3-(pentoxy)propyl]1H-imidazole (Example 29b, 2.12 g, 0.010 mol) in anhydrous tetrahydrofuran (15 ml) was treated with sodium hydride (0.44 g of a 60% dispersion in oil, 0.011 mol) and stirred at room temperature for 1 hour. Ethyl 4-(bromomethyl)benzoate (2.67 g, 0.011 mol) was then added and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give ethyl 4-[[1-(1H-imidazol-1ylmethyl)-2-(pentoxy)ethoxy]methyl]benzoate as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#N.Cl.[OH-].[Na+]>>[NH:14]([C:12]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1)[C:15]([NH2:17])=[NH:16]
Reactant: N#CNC(=N)N
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 17.7 %

Procedure:
A mixture of 4-nitro-o-phenylenediamine (15.3g 0.1 mol), cyanoguanidine (9.25g 0.11 mol) and dilute hydrochloric acid (40 ml, 0.2 mol) was heated under reflux for 11/2 hours. The reaction mixture was cooled, basified with dilute sodium hydroxide, and filtered. The resulting solid was washed well with water (ca 500 ml), dried in vacuo and boiled with ethanol to yield 2-guanidino-5-nitrobenzimidazole (3.90g; 20%) as pale yellow microcrystals m.p. 305°-307°C.