Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:28][O:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:21][CH:20]=1)([OH:25])=[O:24]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Product: O=C(O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 153.4 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy) propanamide (38.1 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (29.7 mg).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=[O:10]>CC#N>[Cl:4][C:3]([Cl:6])([Cl:5])[C@@H:2]1[N:7]2[CH2:14][CH2:13][CH2:12][C@H:8]2[C:9](=[O:10])[O:1]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 81.6 %

Procedure:
22 ml (225 mmol, 2.5 eq) chloral was added to a suspension of 10.470 g (90.94 mmol, 1.0 eq) L-proline (102) in 45 ml MeCN at RT, and the obtained solution was stirred for 19.5 h at RT. The solvent was removed at reduced pressure and the residue dissolved and filtered in 100 ml DCM. The filtrate was concentrated, and this process was repeated three more times. 18.141 g (74.20 mmol, 82%) of the product 103 was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:12])[CH3:13])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.62 g of the compound obtained in Step 86-1 in DMF (30 ml) was added sequentially 1.29 g of K2CO3 and benzyl bromide (1.1 ml), and the reaction mixture was stirred at room temperature for 3 hours. The solution was cooled on ice, then, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with EtOAc. The combined organic layer was washed with water and saturated brine, dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=1/1; v/v) to obtain 2.36 g of the title compound (colorless oil).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:22]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](O)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:24]=[CH:25][CH:26]=1)[C:14]2=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:43])=O>>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36]([Cl:43])=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Product: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1

Procedure:
Prepared by the method of Example 15a), from 2-[3-(5-benzyloxycarbonyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylic acid (2.50 g, 5.0 mmol) and oxalyl chloride (2.19 ml, 25 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][CH2:24]Br>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCBr
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 28.8 g of 4-benzyloxy-3-hydroxy-benzaldehyde in 100 ml of dimethylformamide is added dropwise to a suspension of 5.54 g of NaH (60% dispersion in mineral oil) in 150 ml of absolute dimethylformamide. The reaction mixture is stirred at room temperature. After 30 minutes, a solution of 29 g of 3-methoxybromopropane in 120 ml of dimethylformamide is added thereto, and the mixture is stirred at room temperature for a further 4 hours and is then concentrated by evaporation under reduced pressure. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, dichloromethane), yielding the title compound, which crystallises spontaneously: Rf (dichloromethane/diethyl ether)=0.44.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2OC)=NC=1CC.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH:58]=[CH2:59])[C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[OH:57])=[N:43][C:44]=1[O:45][CH3:46]>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH:58]=[CH2:59])[C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[O:57][CH2:2][CH3:3])=[N:43][C:44]=1[O:45][CH3:46]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 1.11-1.14, 3.04-3.08, 3.37-3.44, 3.60-3.68, 3.84, 4.28-4.30, 5.34-5.37, 5.68-5.71, 5.90-5.99, 6.66-6.73, 7.14-7.26, 7.32-7.40; MS (ESI+) for C24H23Cl2N3O2 m/z 456 (M+H)+.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][O:6][C:5](=[O:9])[N:4]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=O.[Na].[F:23][C:24]([F:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25](=[O:33])[CH2:26]P(=O)(OC)OC>C1COCC1.[Cl-].[Zn+2].[Cl-]>[F:23][C:24]([F:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25](=[O:33])/[CH:26]=[CH:1]/[C@H:3]1[CH2:8][CH2:7][O:6][C:5](=[O:9])[N:4]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Reactant: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1C=O
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Temperature: 60 °C

Procedure:
Horner-Emmons-Smith reaction: to a solution of isopropyl 7-[(4R)-4-formyl-2-oxo-1,3-oxazinan-3-yl]heptanoate (207 mg, 0.691 mmol) in THF (3 mL) was added Zinc chloride (0.5M in THF, 1.52 mL, 0.76 mmol, 1.1 eq) followed by the sodium salt of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate (270 mg, 0.898 mmol, 1.3 eq) as a solid and the mixture was heated to 60° C. o/n and concentrated. The residue was purified by column chromatography (80% ethyl acetate/hexanes) to give the desired product isopropyl 7-{(4R)-4-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-en-1-yl]-2-oxo-1,3-oxazinan-3-yl}heptanoate as a light yellow oil. MS (+ESI): m/z 452 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:25]3[C:16](=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=3)(O)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:4][CH:3]=1.Cl.C1(C)C=CC=CC=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:25]3[C:16](=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:27]3[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)c2ccccc2C(O)(c2ccc(Br)cc2)c2cc3ccccc3cc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Brc1ccc(-c2c3ccccc3c(-c3ccc(Br)cc3)c3cc4ccccc4cc23)cc1
Yield: 81.9 %

Procedure:
Into a 300-cm3 eggplant-shaped flask filled with air, 3.0 g (5.22×10−3 mol) of 5,12-bis(4-bromophenyl)-5,12-dihydroxytetracene synthesized as described above was weighed. Into the eggplant-shaped flask, 150 cm3 of acetic acid, which was used as a solvent, was poured, whereby an acetic acid solution was prepared. Stannous chloride and a 35% of aqueous solution of hydrochloric acid were mixed at a weight ratio of 1:1, whereby a hydrochloric acid solution of stannous chloride was prepared. To the acetic acid solution, 20 cm3 of the hydrochloric acid solution was added. The solution mixture was subjected to reaction for three hours at room temperature. The reaction mixture was transferred to a separatory funnel. Toluene was added to the reaction mixture. This mixture was sufficiently washed with distilled water. The organic layer in the separatory funnel was dried with 5 g of magnesium sulfate. The solvents were removed from the organic layer in an evaporator, whereby a white solid was obtained. The white solid was purified by silica gel chromatography using a mixture containing toluene and hexane at a ratio of 1:2 and reprecipitation using dichloromethane and hexane, whereby 2.3 g of 5,12-bis(4-bromophenyl)-tetracene was obtained as shown in FIG. 6. The yield of 5,12-bis(4-bromophenyl)-tetracene was 82%.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:13]=[CH:14]4)[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: COC(=O)c1ccccc1-n1ccc2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using methyl 2-iodobenzoate and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 510.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:18]([S:25](Cl)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([S:25]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (3.04 g, 12.1 mmol) in pyridine (30 mL) cooled to 0° C. was added benzylsulfonylchloride (2.67 g, 15.1 mmol). While stirring of the reaction mixture the precipitate formed. After one hour the solvent was evaporated under reduced pressure and the product was partitioned between dichloromethane and 10% KHSO4 solution. The aqueous phase was extracted with dichloromethane twice. The combined organic phases were dried over a drying agent and the solvent was evaporated under reduced pressure. A brown-reddish product obtained was suspended in ethyl acetate and heated to reflux, then cooled and filtered to give 2.56 g (6.52 mmol) of a pink product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:40](O)(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1ccncc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1ccncc1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure E using isonicotinic acid. The final product was obtained in 66% yield.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39][OH:40])[CH2:34]1>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][O:36][C@H:35]([CH2:39][OH:40])[CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:32])[F:30])[CH:3]=1
Reactant: OCC1CNCCO1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and (2S) Morpholin-2-yl-methanol following General Procedure B.
Reaction SMILES: [Li+].[OH-].[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][S:11][C:12]2[S:13][CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[C@@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:6]([OH:30])[CH2:5]1>>[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][S:11][C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[C@@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:6]([OH:30])[CH2:5]1
Reactant: CCCCCCCC[C@@H]1[C@@H](CCSc2nc(C(=O)OCC)cs2)[C@H](Cl)C[C@H]1O
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCC[C@@H]1[C@@H](CCSc2nc(C(=O)O)cs2)[C@H](Cl)C[C@H]1O
Yield: 106.7 %

Procedure:
The previously described LiOH procedure (U.S. Pat. No. 7,091,231) was used, starting with 13 mg 6-7 and providing 6-8 (13 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>C1CCCCCC=1>[O:1]=[C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: Oc1cccc2c1CCCCC2
Agent: C1=CCCCCC1
Product: O=C1CCCC2=C1CCCCC2
Yield: 49.5 %

Procedure:
Prepared as in Example 37, using 4-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene as the starting material, which was prepared as follows: 8 g (71.4 mmol) 2-hydroxypyrone (Syn. Commun., 5, 461, (1975)) and 20 mL cycloheptene were reacted in a sealed tube at 150° C. for 24 h to give 1-oxo-3,4,6,7,8,9-hexahydro-5H-benzocycloheptene in 49.5% yield, followed by reaction with isopropenyl acetate to afford the enol acetate and treatment with 2,3-dichloro-5,6-dicyanobenzoquinone at 90° C. for 1.5 h (see J. Med. Chem., 37, 3803 (1994)) to afford 4-acetoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene in 69% yield as an oil. Hydrolysis with 3.7 equivalents of powdered potassium hydroxide in ethanol at room temperature for 2 h gave a 44% yield of the desired 4-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene after purification by column chromatography as a white solid. The remaining steps in the sequence then followed Example 48. The final step proceeded in 89% yield to give the product as an amorphous solid as the hydrochloride salt from ether.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:14]1[C:15]([NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]([C:17]1[N:18]=[CH:19][C:14]2[CH:3]=[C:2]([CH2:1][C:4]3[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=3)[N:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]=2[N:16]=1)#[N:21]
Reactant: C#CCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cn1c(Cc2ccc(C(=O)O)cc2)cc2cnc(C#N)nc21
Temperature: 75 °C
Yield: 51 %

Procedure:
To a solution of 4-prop-2-ynyl-benzoic acid (6.3 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (4.8 mmol) in DMF (30 ml), triethylamine(14.4 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.48 mmol) and copper (I) iodide (0.96 mmol) are added. The reaction mixture is heated at 75° C. ca. for 18 h. Saturated aqueous solution of ammonium chloride is added to the reaction mixture and then aqueous layer is extracted with two 150 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product which is purified by silica gel column chromatography. Yield: 51%. Rf=0.18 (AcOEt only)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[C:41]([O:49][C:50](=[O:52])[CH3:51])=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43](O)=[O:44])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[C:41]([O:49][C:50](=[O:52])[CH3:51])=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:44])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.7 %

Procedure:
4-Trifluoromethylaniline (0.159 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.271 mmol, 51%).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[C:11](=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:22]([O-])=O)[CH:9]=2)[N:4]=1>CO.Cl>[F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[C:11](=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:22])[CH:9]=2)[N:4]=1
Reactant: Cc1ccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c(C)c1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2c(CF)nc3ccc(N)cc3c2=O)c(C)c1
Yield: 66.1 %

Procedure:
2.0 g of 2-fluoromethyl-3-(2,4-dimethylphenyl)-6-nitro-4(3H)-quinazolinone are suspended in 35 ml of methanol, and a solution of 5.4 g of stannous chloride dihydrate in 5 ml of conc. hydrochloric acid is added dropwise thereto under ice-cooling and stirring. Then, the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure to remove methanol, and water is added to the residue. The aqueous mixture is neutralized with sodium bicarbonate, and chloroform is added thereto. After stirring the mixture, insoluble materials are filtered off. The chloroform solution is separated from the filtrate and concentrated under reduced pressure to give a crystalline residue. The thus-obtained crystals (1.4 g) are recrystallized from isopropanol. 1.2 g of 2-fluoromethyl-3-(2,4-dimethylphenyl)-6-amino-4(3H)-quinazolinone are obtained as pale yellow prisms.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19](=[O:30])[C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[C:21]=1F)[C:14]([O:16]CC)=[O:15])C>C(O)C>[F:26][C:24]1[CH:25]=[C:20]2[C:21](=[C:22]([F:28])[C:23]=1[F:27])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:19]2=[O:30]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 97.9 %

Procedure:
5.7 g of 4-fluoroaniline are added dropwise to a solution of 16 g of ethyl 3-ethoxy-2-(2,3,4,5-tetra-fluorobenzoyl)-acrylate (5) (X1 --X4 =F) (Appln. Ser. No, 756,469, filed July 18, 1985, now Pat. No. 4,952,695) in 50 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 50 ml of ice-water are added and the precipitate is filtered off cold with suction, rinsed with water and dried at 50° C. over calcium chloride in vacuo. 16.5 g of (6) (R=4-fluorophenyl, X1 --X4 =F) of melting point 93°-95° C. are obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:21](=[O:22])[C:20]2[CH:19]=[C:18]([C:17]([F:32])([F:31])[F:16])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cnccc1-c1ncccc1F
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ncccc1F

Procedure:
The title compound was prepared in analogy to example 55, from (3-fluoro-[2,4]bipyridinyl-3′-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Brown Solid (13%). MS (ESI): m/z=444.4 [M+H]+.