Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5](C#N)[C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[K+].C(O)CO>O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]2([CH2:5][C:4]([OH:22])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C#N)C1(c2ccc(OC)cc2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(C2(CC(=O)O)CCCCC2)cc1
Temperature: 180 °C
Yield: 79.8 %

Procedure:
A mixture of cyano-[1-(4-methoxy-phenyl)-cyclohexyl]-acetic acid ethyl ester (1.84 g), potassium hydroxide (1.27 g), ethylene glycol (5 ml) and water (0.025 ml) was heated to 180° C. for 21 h. After cooling to room temperature, water was added and washed with diethyl ether. The aqueous phase was acidified using concentrated HCl and extracted with dichloromethane. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound as an off-white solid (1.21 g), MS (ESI−): m/z=247.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[CH3:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=1)=[O:24]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:30][CH:29]=2)[N:32]=1
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1
Yield: 75.2 %

Procedure:
The title compound was prepared according to the procedure described in step-1 and step-2 of Intermediate-9 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.300 g, 4.2 mmol) and tert-butyl 2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-7, 1.150 g, 3.8 mmol) in TFA (5-7 mL) and DCM (40 mL). The reaction mass was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 1.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 4.44 (d, J=5.7 Hz, 2H), 7.49 (t, 1H), 7.66 (d, J=8.7 Hz, 2H), 8.04-8.13 (m, 4H), 10.07 (m, 1H), 12.69 (s, 1H); MS (m/z): 453.14 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]>>[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:44])=[O:43])=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-Butoxy-N-[2-[(phenylsulfonyl)amino]4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 4-n-butoxybenzenesulfonylchloride (59 mg, 0.239 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z =Found: 545.2; Calcd 545.18; 1H-NMR δ 7.73-7.45 (m, 7H), 6.95-6.91 (m, 2H), 6.72-6.70 (m, 1H), 4.00 (t, 2H), 3.29-3.24 (m, 8H), 1.79-1.70 (m, 2H), 1.55-1.43 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:28](=[O:31])[CH2:29][CH3:30])[C:24](=[O:27])[CH2:25][CH3:26])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24](=[O:27])[CH2:25][CH3:26])[C:28](=[O:31])[CH2:29][CH3:30])=[CH:13][CH:14]=1
Reactant: CCC(=O)C(CCCCC=CCCc1ccc(OCc2ccccc2)cc1)C(=O)CC
Agent: [Pd]
Product: CCC(=O)C(CCCCCCCCc1ccc(O)cc1)C(=O)CC

Procedure:
[I; Ar is 4-C6H5CH2C6H4, R0 is H, R' and R" are CH3CH2CO, Y is CH2CH2CH2CH2CH2CH2 ] was prepared by hydrogenating 4-[8-(4-benzyloxyphenyl)-5-octenyl]-3,5-heptanedione in the presence of palladium-on-carbon catalyst, and obtained as colorless crystals, m.p. 164°-165° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:38](=[NH:43])(OCC)[CH3:39].C(N(CC)CC)C>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[NH:43][C:38]([CH3:39])=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nnc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.025 g, 0.048 mmol), ethyl acetimidate hydrochloride (6.6 mg, 0.053 mmol), triethylamine (11 mg, 0.11 mmol), and MeCN (0.15 mL) was heated in a microwave reactor at 200° C. for 1 h. The reaction was partitioned between water and DCM, and the product was extracted with DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatograph, elution with mixtures of EtOAc in hexanes to provide the title compound. LC/MS: m/e 543.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.12 (1H, s), 7.92 (1H, s), 7.57 (1H, d, J=6.8 Hz), 7.20-7.60 (3H, m), 6.87-6.93 (3H, m), 4.40-5.20 (3H, br), 2.53 (3H, s), 1.22 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:7]2
Reactant: COc1ccc2ccccc2c1Cl
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(Cl)c(OC)ccc2c1

Procedure:
reacting under Friedel-Crafts conditions 1-chloro-2-methoxy-naphthalene with propionyl chloride in methylene chloride at a temperature of from about 0° C. to ambient temperature in the presence of aluminum chloride to form 1-(5-chloro-6-methoxy-2-naphthyl)-1-propanone,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:14][C:15]1[C:20]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Cc1ncccc1O
Product: Cc1ncccc1OC[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 55.1 %

Procedure:
An ice-cooled solution of 1-t-butoxycarbonyl-2-(S)-azetidinemethanol (from Example 7b, 0.623 g, 3.33 mmol) was allowed to react with 2-methyl-3-hydroxypyridine (0.399 g, 3.66 mmol) under the conditions of Example 2a to yield the title compound (0.511 g, 55%). MS (DCI/NH3) m/e: 279 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.10 (dd, J=4.4, 1.5 Hz, 1H), 7.15-7.06 (m, 2H), 4.54-4.53 (m, 1H), 4.35-4.34 (m, 1H), 4.07 (dd, J=10.3, 2.6 Hz, 1H), 3.96-3.88 (m, 2H), 2.51 (s, 3H), 2.42-2.31 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15](O)[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)[CH3:2].C(N(S(F)(F)[F:38])CC)C.O>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@@H:15]([F:38])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC[C@H](O)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(OC[C@@H](F)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Temperature: -78 °C
Reaction time: 48 h

Procedure:
Using 174 mg of 3-{3-[3-(2,4-dichlorophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester (Production example 279e) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to −78° C. To the solution was added 0.15 ml (diethylamino) sulfur trifluoride, and stirring was continued at room temperature for 2 days. Water was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed. The residue was purified by silica gel column chromatography, to give 79 mg of 3-{3-[3-(2,4-dichlorophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester in the 7:1→5:1 hexane-ethyl acetate fraction. This product was dissolved in 4 ml of ethanol and 0.5 ml of tetrahydrofuran and 0.5 ml of 1N lithium hydroxide were added, and stirring was continued overnight at room temperature. The solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed. The residue was purified by silica gel column chromatography, to give 61 mg of the title compound in the 3:1→1:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH2:14][OH:15])[CH:5]=1)[CH3:2]>ClCCl.C(O)C.O=[Mn]=O>[CH2:1]([O:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(CO)cc2oc(=O)[nH]c12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCO
Product: CCOc1cc(C=O)cc2oc(=O)[nH]c12
Temperature: 40 °C
Yield: 77.5 %

Procedure:
To a solution of 4-ethoxy-6-hydroxymethyl-3H-benzooxazol-2-one (0.69 g, 3.30 mmol, 1.0 equiv) in a mixture of dichloromethane (40 mL) and ethanol (5 mL) was added activated MnO2 (1.15 g, 13.2 mmol, 4.0 equiv). The reaction mixture was heated to 40° C. for 2 h, filtered through Hyflo Super Cel and concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (1:1) to yield 0.53 g (78% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.43 (t, J=7.0 Hz, 3H), 4.23 (q, J=7.0 Hz, 2H), 7.38 (s, 1H), 7.42 (s, 1H), 9.87 (s, 1H), 12.28 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.41, 64.63, 104.07, 109.32, 125.20, 131.05, 143.13, 143.88, 154.21, 191.11. MS (ISP): 208.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[C:18]([F:29])=[C:19]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=2)[O:23][CH2:22][CH2:21][CH2:20]3)=[N:11]1)=[O:4].CO.[OH-].[Na+]>C(O)(=O)C>[F:29][C:18]1[C:17]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:34](=[CH:35][CH:36]=2)[C:37](=[NH:38])[NH:40][CH2:39]3)[C:12]2[NH:13][C:14](=[O:15])[N:10]([C:6]3[N:7]=[CH:8][S:9][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)=[CH:26][C:25]([O:27][CH3:28])=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][O:23]2
Reactant: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-(5-fluoro-8-methoxychroman-6-yl)methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid methyl ester (74 mg) and methanol (2.0 mL) there was added aqueous 5N sodium hydroxide (111 μL), and the mixture was stirred at room temperature for 3 hours and 15 minutes. After adding acetic acid (52 μL) to the mixture, the solvent in the mixture was distilled off under reduced pressure. Dichloromethane (2.0 mL) was added to the residue, TFA (400 μL) was added to the resulting solution and the mixture was stirred at room temperature for 5 hours. Dichloromethane (50 mL) was added to the mixture, which was then stirred at room temperature for 14 hours. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (21 mg).
Reaction SMILES: Cl.N[C:3]1[O:4][C:5]2[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1.C[OH:29]>O>[C:24]([C:17]1[CH:18]=[C:19]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:5]2[O:4][C:3](=[O:29])[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=3)[C:6]=2[CH:16]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(-c2c(N)oc3c(C(C)(C)C)cc(C(C)(C)C)cc23)cc1C
Reactant: CO
Agent: Cl
Solvent: O
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.35 ml (0.70 mmol) of 2N HCl is added at room temperature to a solution of 0.22 g (0.63 mmol) of 2-amino-5,7-di-tert-butyl-3-(3,4-dimethylphenyl)-benzofurane [compound (302), Table 3, prepared according to Example 2a] in 5 ml methanol and stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted three times with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 200 mg (96%) of 5,7-di-tert-butyl-3-(3,4-dimethylphenyl-3H-benzofuran-2-one (compound (102), Table 1), m.p. 130-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[Cl:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16]Cl>>[Cl:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: OC(CCl)CCCl
Product: OC(CCl)CCOc1ccc2c(c1)OCCC2

Procedure:
The starting 1-chloro-4-(3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-butanol was prepared according to example 1 (b) from 7-hydroxy-3,4-dihydro-2H-1-benzopyrane (J. Chem. Soc. 1190, 1958) and 1,4-dichloro-2-butanol (m.p. 78°-80° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)CCN(C)C.CN1CCCC1=O.[Br:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[C:42]([F:48])[CH:41]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:16]([CH:15]([CH:44]([C:43]1[CH:46]=[CH:47][C:40]([Br:39])=[CH:41][C:42]=1[F:48])[OH:45])[C:14]([N:3]1[CH:2]([CH3:1])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC1C(c2ccccc2)OC(=O)N1C(=O)C(Cc1ccccc1)C(O)c1ccc(Br)cc1F
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4R, 5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1.50 g, 4.8 mmol) in dichloromethane (23 mL) at −70° C. was added titanium tetrachloride (0.6 mL, 5.3 mmol) giving a yellow-orange solution which was stirred for 15 minutes at −70° C. N,N,N′,N′-Tetramethylethylenediamine(2.2 mL, 15 mmol) was added over 10 minutes giving a dark red reaction mixture which was stirred for 70 minutes at −78° C. 1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes at −70° C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol) in dichloromethane (5 mL) was added dropwise while maintaining a reaction temperature of less than or equal to −68° C. The reaction mixture was stirred at −70° C. for 60 minutes and then allowed to warm to 0 C. over 90 minutes, at which point it was quenched with 15 mL of saturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixture was stirred overnight at room temperature and filtered. The phases were separated and the organic phase was washed three times with water and once with brine, dried over magnesium sulfate, and concentrated under vacuum to 2.76 g of an oil containing the title compound and 1.2 equivalents of 1 -methyl-2-pyrrolidinone: 1H NMR (400 MHz, CDCl3) 67 7.48 (t, J=8.1 Hz, 1 H), 7.09-7.34 (m, 1 2H), 5.35 (d, J=7.3 Hz, 1 H), 5.32 (d, J=4.9 Hz, 1 H), 4.89-4.92 (m, 1 H), 4.51-4.55 (m, 1 H), 3.65 (bs, 1 H), 3.35 (dd, J=7.1, 7.1 Hz, 2H), 3.03-3.06 (m, 2 H), 2.81 (s, 3H), 2.34 (dd, J=8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[C:21](=[O:28])[N:20]4[CH2:29][CH2:30][CH2:31][C@H:19]4[C:18]=23)[O:11][N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>CO.[Pd]>[CH2:1]([N:4]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[C:21](=[O:28])[N:20]4[CH2:29][CH2:30][CH2:31][C@H:19]4[C:18]=23)[O:11][N:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)n1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)n1
Yield: 59.5 %

Procedure:
1.8 g (4 mmol) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one were dissolved in 50 ml of methanol and hydrogenated at normal pressure and room temperature in the presence of 60 mg of 5% palladium-charcoal. The catalyst was separated and the solution was evaporated. By chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19.5/0.5 there was obtained 1 g (60%) of (S)-1-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 198°-201°.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)(=[O:4])=[O:3].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)Oc1cccc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(OS(C)(=O)=O)c2)CC1
Yield: 125 %

Procedure:
The above prepared 3-methanesulfonyloxy-benzoic acid (0.400 g, 1.85 mmol) was condensed with 4-amino-1-BOC-piperidine (0.370 g, 1 eq.) in the presence of 1.1 eq. of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.899 g) and 1.2 eq. of N-ethyl-diisopropylamine (0.38 ml) in 9 ml of abs. THF during one night at ambient temperature. Pouring onto crashed ice/AcOEt, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3), yielded 0.920 g of the title compound as white foam, contaminated with some reagent derived impurities, but sufficiently pure for the next steps.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>C(O)(C)C>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(I)c3)c2c1
Yield: 26.8 %

Procedure:
3-Iodoaniline (12.57 grams, 57 mmol) was reacted with 4-chloro-6-nitroquinazoline (4 grams, 57 mmol), in iso-propylalcohol, as is described hereinabove, to give 4-[(3-iodophenyl)amino]-6-nitroquinazoline (5.99 grams, 78% yield), which was thereafter reacted (620 mg, 1.58 mmol) with hydrazine hydrate and Raney®Nickel, according to the procedure described hereinabove, to give 4-[(3-iodophenyl)amino]-6-aminoquinazoline (180 mg, 31% yield).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.CN1CCCN(C)C1=O.C([Li])CCC.[F:32]/[C:33](=[C:36](/[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([CH3:51])([CH3:50])[CH:42]=[C:41]2[CH:52]([CH3:54])[CH3:53])\[CH3:37])/[CH:34]=O>C1COCC1>[F:32]/[C:33](=[C:36](/[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([CH3:51])([CH3:50])[CH:42]=[C:41]2[CH:52]([CH3:54])[CH3:53])\[CH3:37])/[CH:34]=[CH:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (240 mg, 0.91 mmol) in THF (10 mL), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.13 mL) under argon at −78° C. was slowly added n-butyl lithium (1.6 M in hexanes, 0.60 mL, 0.96 mmol). The resulting mixture was stirred at −78° C. for 15 min before a solution of (2E)-2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-enal (Compound 95, 100 mg, 0.31 mmol) and THF (3 mL) was added via cannula. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl, and the product was extracted with diethyl ether. The combined ethereal layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexane) to yield the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][O-:16].[Na+]>O1CCCC1>[CH3:15][O:16][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C[O-]
Reactant: CC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=C(C)C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
A solution of 2-chloro-3-methyl-1,4-naphthoquinone (10.3 g) in tetrahydrofuran (100 mL) was treated dropwise with a solution of sodium methoxide (320 g) in tetrahydrofuran (25 mL) at room temperature. After stirring overnight, the mixture was evaporated, and the residue was taken up in ether. The organic layer was washed with brine, dried, filtered and evaporated. Chromatography over silica gel gave 2-methoxy-3methyl-1,4-naphthoquinone, m.p. 93°-94° C.