Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)[CH2:2]1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:11][CH:6]1[CH2:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4][C:5]1=[O:9]
Reactant: O=C1CCCC2(CC2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCC2(CC2)CC1=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Spiro[2.5]octan-5-one (2.4 g, 19.32 mmol) was dissolved in THF (100 mL) and cooled to −75° C. At that temperature LHMDS 1M in THF (24 mL, 24 mmol) was added dropwise over 15 minutes. The resulting pale yellow solution was stirred 1 hour at −75° C. Iodomethane (1.3 mL, 21.26 mmol) was added and stirring was continued at −75° C. for another hour before letting the mixture warm up to RT. The reaction was quenched by addition of saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The remaining yellow oil was purified by SiO2 chromatography (330 g SiO2, hexanes/EtOAc 0 to 3% EtOAc) to give 0.93 g of racemic 6-methyl-spiro[2.5]octan-5-one as a colorless liquid (35% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[O:6]C(C)C.C(Cl)(Cl)Cl.C[Si](Br)(C)C>C(O)(C)C.C1OC1C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:6])[OH:10]
Reactant: CC(C)OP(=O)(CCCN)Cc1ccccc1
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: NCCCP(=O)(O)Cc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 5.7 g (0.0224 mol) of isopropyl 3-aminopropyl(benzyl)phosphinate in 50 ml of chloroform 9.91 ml (0.0922 mol) of trimethylsilylbromide are added raising the temperature to 44°. The reaction mixture is stirred at 50° for 4 hours and then at room temperature overnight. Removal of the chloroform and excess trimethylsilylbromide under reduced pressure yields an oil which is taken up in isopropanol and 20 ml of propylene oxide. After stirring for 10 minutes, a white solid precipitates. The solid is filtered off and dried over phosphorous pentoxide yielding 3-aminopropyl(benzyl)phosphinic acid, m.p. 278-280°.
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].C(=O)([O-])O.[Na+].[CH3:10][C:11]1([CH3:19])[CH2:16][C:15](=O)[CH2:14][C:13](=[O:18])[CH2:12]1>O>[O:4]=[C:3]1[C:14]2[CH:15]=[CH:16][O:18][C:13]=2[CH2:12][C:11]([CH3:19])([CH3:10])[CH2:2]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a mixture of 24 ml of water and 6 ml of 40% aqueous solution of chloroacetaldehyde was added 0.7 g (8 mmoles) of sodium hydrogencarbonate while cooling with ice. To the reaction mixture were added dropwise 4.2 g (30 mmoles) of 5,5-dimethyl-1,3-cyclohexanedione and 40 ml of aqueous solution containing 2.3 g (27 mmoles) of sodium hydrogencarbonate while cooling with ice at a rate of 0.4 ml/minute. The reaction mixture was maintained at a pH of from 5.7 to 8.0 throughout the reaction. After completing the dropping, the reaction mixture was stirred at a room temperature overnight, and then treated in the same manner as in Example 1 to give 2.36 g (yield: 48.2%) of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydrobenzofuran being a colorless oily material (boiling point: 78° C./0.7 mmHg).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19]([O:21][C:22](=[O:41])[CH2:23][N:24]([C:31](=[O:40])[C:32]1[CH:37]=[C:36]([NH2:38])[CH:35]=[C:34]([NH2:39])[CH:33]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:20]>>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:41])[C:31](=[O:40])[C:32]1[CH:37]=[C:36]([NH:38][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:35]=[C:34]([NH:39][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:33]=1)[CH3:30]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(N)cc(N)c1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1

Procedure:
The reaction of palmitoyl chloride with N-(3,5-diaminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as in Example 54 gave N-(2-ethoxy-2-oxoethyl)-N-[3,5-bis(1-oxohexadecylamino)benzoyl]glycine ethyl ester as an oil after chromatography on silica gel using 35% ethyl acetate-hexane.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:39][CH:40]=1
Reactant: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccc(Cl)nc2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from 1-{4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one (example 31) and 2-chloropyridine-5-boronic acid to afford the desired product as a light-brown foam (43%). MS (ISP): 565.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH:12](O)[CH2:13][Cl:14].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH2:12][CH2:13][Cl:14]
Reactant: O=C1Cc2cc(C(O)CCl)c(Cl)cc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A 2 L round-bottom flask is loaded with 300 g (1.22 mols) of 6-chloro-5-(2-chloro-1-hydroxy-ethyl)-1,3-dihydro-indol-2-one and 1140 ml of trifluoroacetic acid, under nitrogen atmosphere. The mixture is stirred at room temperature for 1 h, then heated to about 35-40° C. 214 ml (1.34 mols) of triethylsilane are then dropped therein in approx. 1 hr 30 min, keeping stirring for 12-14 h. Separately, a round-bottom flask is loaded with 3000 g of a water/ice mixture and the reaction mixture is carefully dropped therein, in about 1 hr 30 min, under strong stirring. The resulting white suspension is stirred for 30 min, then filtered, washed with purified water (4×500 ml) and heptane (400 ml), then dried at 60° C. under vacuum to afford 281 g of 6-chloro-5-(2-chloro-ethyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7](=[O:33])[C@H:8]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([N+:19]([O-])=O)[CH:11]=1>[Zn].CO>[CH3:5][O:6][C:7](=[O:33])[C@H:8]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:19])[CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solid ammonium formate (2.27 g, 36 mmol) was added in small portions at 0° C. to a methanol (50 mL, degassed with nitrogen for 2 h) suspension of (R)-2-benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-propionic acid methyl ester (1.45 g, 3.6 mmol) and zinc powder (1.41 g, 21.6 mmol). The resulting mixture was stirred at room temperature overnight. The solvents were removed in vacuo and then toluene (30 mL, degassed) and ethyl acetate (30 mL, degassed) were added, followed by acetic acid (3 mL). The mixture was further diluted until all organic solids dissolved, then it was washed with water, brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo to afford the title compound containing 1 equivalent of acetic acid as a reddish gummy solid (85%). Mass Spec.: 344.18 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[NH:5][CH2:4]1.[N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:35])[C@H:30]([C:32](O)=[O:33])[CH3:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:39]([O:38][C:36](=[O:37])[N:29]([C@H:30]([C:32](=[O:33])[NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[NH:5][CH2:4]1)[CH3:31])[CH3:35])([CH3:40])([CH3:41])[CH3:42]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)CNc2cc(C#N)ccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a stirred solution of (S)-3-amino-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5 tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (305 mg, 0.778 mmol) in DMF (10 mL) was added Boc-N-Me-Ala-OH (173.912 mg, 0.856 mmol), HOBT (115.645 mg, 0.856 mmol) and DIPEA (0.67 mL, 3.89 mmol). After 10 min, the mixture was cooled to 0° C. and HBTU (324.63 mg, 0.856 mmol) was added. After 2 h, the mixture was diluted with ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford the title compound (390 mg, 92.54%) as an off white solid. LC-MS: 542.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-])=O)=[CH:7][C:5]=2[N:6]=1>CC(O)=O.CCOC(C)=O.[Fe]>[CH:7]1[C:8]([NH2:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]2[N:3]=[C:2]([Cl:1])[NH:6][C:5]=12
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc2[nH]c(Cl)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1.213 g (5.0 mmol) of 2-chloro-5,6-dinitrobenzimidazole (22) and 1.398 g (25 mmol) of iron powder in 50 mL of AcOH was stirred at room temperature for 4 h. The reaction mixture was diluted with 100 mL of EtOAc, filtered, and the solid was washed with portions of EtOAc (total EtOAc used ~ 100 mL). The filtrate and washings were combined and washed with H2O (100 mL×3). The H2O layer was extracted with 100 mL of EtOAc. The EtOAc solutions were combined, evaporated, coevaporated with toluene (10 mL×3), MeOH (10 mL×2) to give a brown solid.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C@@H:8]([O:47]C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19]([N:22]2[CH2:42][CH2:41][C:25]3([N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[NH:27][C:26]3=[O:40])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[C:13]([CH3:43])[CH:12]=1)(=O)C>CO>[OH:47][C@H:8]([CH2:7][OH:6])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19]([N:22]2[CH2:23][CH2:24][C:25]3([N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[NH:27][C:26]3=[O:40])[CH2:41][CH2:42]2)(=[O:21])=[O:20])=[C:13]([CH3:43])[CH:12]=1
Reactant: CC(=O)OC[C@H](CN(C(C)=O)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(c2ccc(C(F)(F)F)cc2)NC3=O)c(C)c1)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC[C@H](O)CO)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1ccc(C(F)(F)F)cc1)NC2=O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
A 1.2 M aqueous KOH solution (0.5 mL) was added to a solution of acetic acid (S)-1-acetoxymethyl-2-[acetyl-(3-methyl-4-{2-[4-oxo-2-(4-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-amino]-ethyl ester (40.8 mg, 0.0587 mmol) in MeOH (3 mL). The reaction mixture was stirred at 50° C. for 1.5 hours and then cooled to room temperature. Dowex 50W×4 (237.6 mg) was added. The mixture was further stirred at room temperature for two hours and then filtered, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CH2Cl2/MeOH=10/1) to give 8-{2-[4-((S)-2,3-dihydroxy-propylamino)-2-methyl-phenyl]-ethanesulfonyl}-2-(4-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a white powder (30.3 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:18])[C:14]([F:17])([F:15])[F:16]
Reactant: COc1ccc(C(=O)[C@H]2CCCN2C(=O)C(F)(F)F)cc1OC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C[C@H]2CCCN2C(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.2 %

Procedure:
(R)-2-(3,4-dimethoxybenzoyl)-1-trifluoroacetylpyrrolidine (4.9 g, 0.015 mol) was dissolved in 50 mL dry CH2Cl2 in a 500 mL round-bottom flask. To the solution was added triethylsilane (20 g, 0.172 mol) and BF3.Et2O (50 mL). The reaction mixture was stirred at room temperature for 3 days, after which time a saturated aqueous solution of potassium carbonate was added cautiously in a dropwise manner. When no more gas was evolved, 100 mL CH2Cl2 was added. The mixture was then shaken. The triphasic mixture was filtered through a glass fritted funnel, and the organic layer separated and dried with MgSO4. Removal of the solvent in vacuo yielded 3.2 g of (R)-2-(3,4-dimethoxybenzyl)-1-trifluoroacetylpyrrolidine (68% yield), as an oil which could be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)(Cl)=O.[F:28][C:29]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:30]=1[NH2:31]>CN(C=O)C.C(O)(C)C>[F:28][C:29]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:30]=1[NH:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCCN1CCOCC1
Yield: 27.3 %

Procedure:
A mixture of 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (370 mg, 1.16 mmol), thionyl chloride (5 ml) and DMF (3 drops) was heated at reflux for 2 hours and allowed to cool. The excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene. A solution of 2-fluoro-5-hydroxy-4-methylaniline (220 mg, 1.56 mmol) in isopropanol (10 ml) was added to the solid residue and the mixture was heated at reflux for 2 hours and then allowed to cool. The resulting precipitate was collected by filtration, washed with methylene chloride and dried. The impure solid product was treated with aqueous sodium hydrogen carbonate, to give a suspension and the product was recollected by filtration and purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (140 mg, 27%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][CH:12]([NH2:23])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.CN1CCOCC1.Cl.[CH3:32][N:33]([CH3:50])[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:50][N:33]([CH3:32])[C:34]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41]([NH:23][CH:12]([CH3:11])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:42])[CH2:36][CH2:35]1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 0 °C
Reaction time: 144 h
Yield: 24 %

Procedure:
1-Hydroxybenzotriazole (456 mg, 3.38 mmol), DL-α-methyltryptamine (0.142 ml, 1.69 mmol) and N-methylmorpholine (0.375 ml, 3.38 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (500 mg, 1.69 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (687 mg, 3.38 mmol) was added. The reaction mixture was stirred at RT for 6 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. 5 M sodium hydroxide solution (2 ml, 10 mmol) was added to the filtrate and the mixture was diluted with water (200 ml). The product thereby precipitated out as a beige-coloured solid and was to be obtained in a yield of 83% (581 mg). Separation by chromatography on silica gel was carried out with EA/methanol (15:1), (10:1) and (5:1). The less polar diastereoisomer of 2-(4-dimethylamino-4-phenylcyclohexylidene)-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide were thereby obtained as a colourless solid with an m.p. of 184-187° C. in a yield of 24% (165 mg). It was possible to isolate the more polar diastereoisomer of 2-(4-dimethylamino-4-phenylcyclohexylidene)-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide as a colourless oil in a yield of 18% (126 mg).—Both amides were diastereoisomerically pure.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][N:2]([CH3:1])[C:3]2=[O:15]
Reactant: [H][H]
Reactant: Cn1ncc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ncc2c(N)cccc2c1=O
Yield: 94 %

Procedure:
1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of 5-amino-2-methyl-phthalazin-1-one is obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Temperature: 50 °C
Yield: 38.1 %

Procedure:
A mixture of intermediate 1 (3.0 g), potassium carbonate (3.70 g), 1-(chloromethyl)-4-(methylsulfonyl)benzene (2.74 g) and DMF (20 mL) was heated at 50° C. for 24 hours. The mixture was allowed to cool then poured into water (50 mL) and extracted with dichloromethane (100 mL). The extracts were combined, evaporated under reduced pressure and the residue purified (SiO2 chromatography, eluting with 2% methanol in dichloromethane) to give the sub-titled compound (2.0 g).
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.[O:12]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C(O)C>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.5 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22.4 g, 0.117 mol) was added to a solution of 2-phenoxybenzoic acid (25.0 g, 0.117 mol) and 1-hydroxybenzotrizole (15.8 g, 0.117 mmol) in DCM (80 ml) and N,N-dimethylformamide (160 ml). The reaction mixture was stirred for 20 min at 0° C. A 8.0 M solution of methylamine in ethanol (290 ml, 2.33 mol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was diluted with ethyl acetate (200 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (300 ml). The aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane 1:1 as eluent, to give 22.2 g of N-methyl-2-phenoxybenzamide.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Cl>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Solvent: CCO
Product: [O-][n+]1ccccc1SCc1c(Cl)cccc1Cl

Procedure:
A mixture of 37 gms (0.1 mole) of (40% solution) 2-mercaptopyridine N-oxide, sodium salt and 19.5 gms (0.1 mole) 2,6-dichlorobenzylchloride in 200 ml ethanol is warmed to 65° for thirty minutes, cooled and filtered. The filter cake is washed thoroughly with water and finally with 40 ml of acetone. Vacuum drying of the cake yields 25.3 gms (92% theory) of product, 2-(2,6-dichlorophenylmethylthio)pyridine N-oxide. Melting point 240° - 241° C. Structure confirmed by IR.