Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[Cl:46].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:46][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:36]=1[NH:35][C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1)[C:40]([NH:42][CH3:43])=[O:41]
Reactant: CNC(=O)c1ccc(N)c(Cl)c1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CCCC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-chloro-N-methylbenzamide (1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound (65% yield). MS (ESI) m/z 648.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[N:7][C:8]([CH3:13])=[N:9]2)=[C:4]([NH:14][CH:15]2[C:24]3[C:19](=[C:20]([O:28]C)[C:21]([CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=3)[C:18]([CH3:31])([CH3:30])[CH2:17][C:16]2([C:33]([F:36])([F:35])[F:34])[OH:32])[CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[N:7][C:8]([CH3:13])=[N:9]2)=[C:4]([NH:14][CH:15]2[C:16]([C:33]([F:35])([F:36])[F:34])([OH:32])[CH2:17][C:18]([CH3:31])([CH3:30])[C:19]3[C:20]([OH:28])=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:23][C:24]2=3)[CH:3]=1
Reactant: COc1c(C(C)C)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cc(F)c(F)c2nc(C)ncc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4ccc(C(C)C)c(O)c4C(C)(C)CC3(O)C(F)(F)F)cc(F)c(F)c2n1
Yield: 34 %

Procedure:
100 mg (0.196 mmol) of 1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is treated with BBr3 in dichloromethane as already described several times. After working-up and chromatography, 33 mg (33.9%) of the desired phenol is obtained.
Reaction SMILES: C1N(CCCS(O)(=O)=O)CCOC1.[CH3:14][C@H:15]1[C:22]([S:23][C@@H:24]2[CH2:28][NH:27][C@H:26]([C:29]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([C:38]([OH:40])=[O:39])[CH:37]=3)=[O:30])[CH2:25]2)=[C:21]([C:41]([OH:43])=[O:42])[N:20]2[C@H:16]1[C@@H:17]([C@H:44]([OH:46])[CH3:45])[C:18]2=[O:19].[OH-].[Na+:48]>C(OCC)(=O)C>[CH3:14][C@H:15]1[C:22]([S:23][C@@H:24]2[CH2:28][NH:27][C@H:26]([C:29]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([C:38]([O-:40])=[O:39])[CH:37]=3)=[O:30])[CH2:25]2)=[C:21]([C:41]([OH:43])=[O:42])[N:20]2[C@H:16]1[C@@H:17]([C@H:44]([OH:46])[CH3:45])[C:18]2=[O:19].[Na+:48]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)O)c4)C3)[C@H](C)[C@H]12
Agent: O=S(=O)(O)CCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)[O-])c4)C3)[C@H](C)[C@H]12

Procedure:
To MOPS buffer solution (prepared from 5.5 g MOPS in 100 mL water and pH adjusted to 6-8.5 with sodium hydroxide), diprotected Ertapenem of formula (IV) (10 g) was added and pH adjusted to 7.5 using aqueous sodium hydroxide solution. To this, ethyl acetate (100 mL) was added and stirred to get clear solution at 10-15° C. CO2 gas was purged for 20 mts. To this Pd/C (20 g, 10%) was added and subjected to hydrogenation with 4.5-5.0 Kg pressure at 5-10° C. After completion of reaction, the reaction mass was filtered and the layers separated. The aqueous layer was subjected to carbon treatment and the pH of the filtrate adjusted to 5.5-6.0 followed by stirring with THF (400 mL) for 10 h. The separated oily layer was slowly added into absolute ethanol (100 mL) under stirring at 5° C. The precipitated solid of ertapenem sodium was filtered, washed with ethanol and dried to yield amorphous form of ertapenem sodium. Dry weight: 4.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][CH2:20][C:21]([O:23]CC)=O)=[CH:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:23]=[C:21]1[NH:1][C:2]2[C:3]3[C:4](=[CH:5][N:6]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)CCc1cn(CC(=O)OC(C)(C)C)c2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cn1cc2c3c(cccc31)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-1H-indol-3-yl]propanoate from Step C (1.00 g, 2.89 mmol) in toluene (50 mL) was added p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) and the mixture was heated at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and the mixture was washed with saturated aqueous NaHCO3 (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 92:8, to give the title compound. MS: m/z=301 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cccn(-c2ccccn2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccn(-c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of methyl 2-oxo-1-(pyridin-2-yl)-1,2-dihydropyridine-3-carboxylate (500 mg, 2.17 mmol) and 3 N NaOH (1 mL) and methanol (10 mL) was stirred at rt overnight. To the reaction was added TFA (0.5 mL) and the mixture was concentrated in vacuo. The residue was dissolved in water (3 mL) and i-PrOH (10 mL). The solid which formed was filtered, washed with a small amount of water and i-PrOH, and dried to obtain the acid (260 mg, 55%) as a white solid. 1H NMR (DMF-d7) δ 14.14 (br s, 1H), 8.72 (d, 1H, J=4.9 Hz), 8.62 (dd, 1H, J=7.7, 2.2 Hz), 8.47 (dd, 1H, J=6.6, 2.2 Hz), 8.18–7.98 (m, 2H), 7.67 (dd, 1H, J=7.2, 5.3 Hz), 6.97 (t, 1H, J=6.6 Hz); MS(ESI+) m/z 217.2 (M+H)+.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=C[C:4]=1[C:9]1[C:10]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH:22]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=O.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1.[K]>O>[CH3:48][O:49][CH:50]=[CH:46][C:47]1[CH:6]=[CH:7][CH:8]=[CH:3][C:4]=1[C:9]1[C:10]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH:22]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Reactant: C1CCOC1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: O
Product: COC=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Yield: 87 %

Procedure:
Under the atmosphere of argon, 25.0 g of 9-(2-formylphenyl)phenanthrene, 33.4 g of methoxymethyltriphenylphosphonium chloride and 300 mL of THF were placed, and 11.9 g of potassium t-buthoxide was added at room temperature during stirring. After stirring at room temperature for 2 hours, 200 mL of water was added. The reaction solution was extracted with diethyl ether, and an aqueous phase was removed. An organic phase was washed with water and saturated saline, and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The residues were purified by silica gel column chromatography, whereby 24.0 g (yield 87%) of 9-[2-(2-methoxyvinyl)phenyl]phenanthrene as an intended product was obtained.
Reaction SMILES: C(O[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[CH:14]1([Mg]Cl)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>C(OCC)C>[CH:14]1([Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C1CCCCC1
Reaction time: 6 h

Procedure:
60 ml of dry diethyl ether and 14.0 gram (0.067 mole) of tetraethoxysilane were charged in a 250 ml flask equipped with a reflux condenser and a stirring apparatus in an atmosphere of nitrogen and above prepared solution of cyclohexyl magnesium chloride was slowly added while keeping the internal temperature below 10° C. After completion of addition stirring was carried out at room temperature for 6 hours and at reflux temperature for 2 hours. To the resulting reaction mass 10-20 ml of saturated aqueous ammonium chloride solution was added drop wise to dissolve magnesium salt. The organic layer was separated from the aqueous layer, dried and evaporated to give crude cyclohexyltriethoxysilane. This crude was purified by fractional distillation under reduced pressure, yielding 14.2 gram of pure cyclohexyltriethoxysilane (86% of the theoretical maximum yield based on the amount of tetraethoxysilane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13]CCC(OCCCCCCCC)=O)[CH:6]=1)[CH3:2].N#N.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([SH:13])[CH:6]=1)[CH3:2]
Reactant: CCCCCCCCOC(=O)CCSc1cc(C(=O)OCC)ccc1OC
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(S)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Methoxy-3-(2-octyloxycarbonyl-ethylsulfanyl)-benzoic acid ethyl ester (2.93 g, 7.40 mmol) was dissolved in THF and the mixture was chilled to −78° C. N2 (g) was bubbled through the reaction mixture and potassium tert-butoxide (8.88 mL, 1.0M in THF, 8.88 mmol) was added via syringe over 2 minutes. The reaction was stirred at −78° C. for 1 hour then slowly allowed to warm to 10° C. for 2 hours. The reaction was then quenched with 1N aq. HCl (30 mL) and submitted to standard aqueous workup. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes:MeOH (98:2)) to afford the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:8]3[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=[C:10]([CH3:12])[C:9]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2nc(-c3ccc(F)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-7-hydroxy-4-methyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (70 mg, 0.21 mmol) and glycine (317 mg, 4.23 mmol) in 0.5 M sodium methoxide/methanol (8 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (62 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.01 (br s, 1H), 9.22 (br s, 1H), 8.20 (m, 2H), 7.40 (m, 2H), 4.03 (d, J=5.9 Hz, 2H), 2.86 (s, 3H); MS: (+) m/z 361.87 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Clc1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3Cl)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromochlorobenzene. MS (ESI): mass calcd. for C16H11ClFN3, 299.06; m/z found, 300.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.12 (s, 1H), 7.98 (m, 1H), 7.54-7.44 (m, 1H), 7.41-7.23 (m, 5H), 4.68 (s, 2H).
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.N1C=CN=C1.NCC[CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH:27]=[CH:26]2>CS(C)=O>[N:8]1([C:6]([NH:3][CH2:2][CH2:1][CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH:27]=[CH:26]3)=[O:7])[CH:9]=[CH:10][N:11]=[CH:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: c1c[nH]cn1
Solvent: CS(C)=O
Product: O=C(NCCCOc1ccc2[nH]c(=O)ccc2c1)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of N,N-carbonyldiimidazole (139 g) and imidazole (117 g) in dimethylsulfoxide (2 liters) is added with stirring 6-(3-aminopropoxy)carbostyril (200 g) in portions under ice-cooling. The mixture is further stirred at room temperature for one day, and poured into ice-water. The precipitated crystals are collected by filtration, and washed with water. The crystals thus obtained are further washed successively with ethanol and diethyl ether, and dried to give 6-[3-(1-imidazolyl)carbonylaminopropoxy]carbostyril (162 g) as a white powder.
Reaction SMILES: CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In another embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of toluene to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). Further, reduction of the amine (8) with sodium borohydride in the presence of isobutyric acid will produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 4. Additionally, the conversion of the amine (8) to the cis-cyclohexane derivative (9) is further treated with hydrogen bromide and ethyl acetate in propionic acid to create the hydrobromide salt of the cis-cyclohexane derivative (9). The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium tert-butoxide to afford the trans-cyclohexane derivative (10) as a major diastereomer. After conversion to trans-cyclohexane derivative (10), the compound is subjected to reduction of the ester functionality in compound (10), using potassium borohydride in the presence of lithium chloride, to yield (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11). Generally, the conversion from compound (10) to compound (11) may incorporate tetrahydrofuran as a co-solvent and may be refluxed to afford the desired compound (11) in good overall yield.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH3:13])[C:3]=1[CH:14]=[O:15].CO[C:18]1C=C(C)C=C[C:19]=1C(=O)CC>>[Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH3:13])[C:3]=1[C:14](=[O:15])[CH2:18][CH3:19]
Reactant: CCC(=O)c1ccc(C)cc1OC
Reactant: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Product: CCC(=O)c1c(Cl)nc(-c2ccccc2)n1C

Procedure:
The title compound is prepared from 5-chloro-3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde analogously to 1-(2-methoxy-4-methyl-phenyl)-propan-1-one (Intermediate N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[C:11]([CH:15]=[O:16])=[CH:12][S:13][CH:14]=2)=[CH:4][CH:3]=1.C1(C#CC2C=C(C=O)SC=2)C=CC=CC=1.C(C1C=C(C=O)SC=1)CC1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[C:11]([CH:15]=[O:16])=[CH:12][S:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cscc1C=Cc1ccc(Cl)cc1
Agent: O=Cc1cc(C#Cc2ccccc2)cs1
Agent: O=Cc1cc(CCc2ccccc2)cs1
Product: O=Cc1cscc1CCc1ccc(Cl)cc1
Yield: 72.1 %

Procedure:
4-(4-Chlorophenethyl)thiophene-3-carbaldehyde was synthesized from 4-[2-(4-chlorophenyl)-vinyl]-thiophene-3-carbaldehyde (260 mg, 1.04 mmol) following the conditions used to hydrogenate 4-(phenylethynyl)thiophene-2-carbaldehyde to 4-phenethylthiophene-2-carbaldehyde (Example 1.1.b). Purification by flash chromatography (0-10% EtOAc/heptane) yielded 4-(4-chlorophenethyl)thiophene-3-carbaldehyde (188 mg, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 2.86-2.92 (m, 2H), 3.16-3.22 (m, 2H), 6.91 (dd, J=3.20, 0.82 Hz, 1H), 7.10-7.15 (m, 2H), 7.22-7.27 (m, 2H), 8.11 (d, J=3.11 Hz, 2H), 10.00 (d, J=0.82 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]4[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=4)[CH2:25][CH2:26]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(c1ccc2[nH]ccc2c1)N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
In the manner described in Example 24, indole-5-carboxylic acid (100 mg, 0.62 mmol) and 1-[2-(4-nitrophenyl)ethyl]piperazine (151 mg, 0.64 mmol) gave, after purification by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 ; 95:5:0.5 and trituration with hexane/EtOAc, the piperazine (38 mg, 16%), mp 204°-206° C.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)OC1.[CH3:20][N:21]1[CH2:26][CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:22]1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][N:21]1[CH2:22][CH:23]=[C:24]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[CH2:25][CH2:26]1
Reactant: CN1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)COB(c2cc(N)cc(C(F)(F)F)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CN1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C

Procedure:
3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine (8.8 g, 0.032 mmol) was added to trifluoro-methanesulfonic acid 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (7.91 g, 0.032 mmol) and 2 N Na2CO3 aqueous solution (25 mL) was bubbled through N2 for 5 min. Pd(PPh3)4 (3.7 g, 3.2 mmol) was added and the reaction was heated to 80° C. for 16 h. The reaction was cooled to RT and diluted with Et2O (100 mL). The mixture was filtered through Celite® and the filtrate was washed with NaHCO3 aqueous solution (25 mL) followed by brine (25 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The desired product was isolated by passing through silica gel column chromatography (EtOAc, then (2 M NH3) in MeOH/EtOAc) to provide a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:17])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([O:19][CH3:18])=[O:28])=[CH:26][CH:25]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Into a solution of 6 (8.11 g, 33.0 mmol) in CHCl3 (200 mL) was added 4-amino-benzoic acid methyl ester (5.00 g, 33.0 mmol), EEDQ (9.81 g, 39.6 mmol), and triethylamine (6.9 mL, 49.6 mmol). The solution was stirred at reflux for 19 h before cooling to RT and adding EtOAc. The solution was washed sequentially with 1N HCl, 0.1N NaOH, water, and brine, before drying over MgSO4 and concentrating under reduced pressure to give 7 (12.50 g, 100%). MS: APCI (AP+): 379.3 (M)+, (AP−): 377.3 (M)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[NH2:11][OH:12]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[NH:10])[NH:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCc1ccc(F)cc1
Solvent: CCO
Product: N=C(Cc1ccc(F)cc1)NO
Yield: 99.9 %

Procedure:
A solution of 2-(4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) and 50% aq. hydroxylamine (1.33 g, 20 mmol) in EtOH (10 mL) was stirred at 90° C. for 18 h then cooled and concentrated to afford the title compound (1.68 g, 100% yield) as white solid. 1HNMR (500 MHz, CDCl3) δ: 8.04-7.85 (1H, br s), 7.24 (2H, dd, J=8.6, 5.5 Hz), 7.01 (2H, t, J=8.6 Hz), 4.46 (2H, s), 3.43 (2H, s). LCMS (M+H): 169.14.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23].O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(Cl)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C

Procedure:
33.8 g (0.1 mol) of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux for 3 hours in a mixture of 100 ml of acetic acid, 20 ml of water and 10 ml of concentrated sulphuric acid. After cooling, the mixture is poured onto 100 ml of ice water, and the deposited precipitate is filtered off with suction, washed with water and ethanol and dried in vacuo at 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=CC1CCCCC1
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2C1CCCCC1
Yield: 73.8 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with hexahydrobenzaldehyde as described in Example 11 to give 1-nitro-5-cyclohexyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 150°-152° C. Yield: 73.8%.