Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[CH:18][C:17]([S:30]([C:33]1[CH:34]=[C:35]([CH:55]=[CH:56][CH:57]=1)[C:36]([NH:38][C:39]1[CH:54]=[CH:53][C:42]([CH2:43][CH2:44][NH:45]C(=O)OC(C)(C)C)=[CH:41][CH:40]=1)=[O:37])(=[O:32])=[O:31])=[CH:16][C:15]=2[CH3:58])(=[O:10])[NH2:9]>C(Cl)Cl>[NH2:45][CH2:44][CH2:43][C:42]1[CH:53]=[CH:54][C:39]([NH:38][C:36]([C:35]2[CH:34]=[C:33]([S:30]([C:17]3[CH:18]=[C:19]4[C:14](=[C:15]([CH3:58])[CH:16]=3)[N:13]=[CH:12][C:11]([C:8]([NH2:9])=[O:10])=[C:20]4[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)(=[O:31])=[O:32])[CH:57]=[CH:56][CH:55]=2)=[O:37])=[CH:40][CH:41]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC(=O)OC(C)(C)C)cc5)c4)cc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCN)cc5)c4)cc23)c1
Reaction time: 5 h

Procedure:
TFA (0.5 mL) was added dropwise to a suspension of Intermediate 82 (382 mg, 0.538 mmol) in CH2Cl2 (5 mL) at rt. After stirring for 5 h, the reaction was concentrated in vacuo to give a brown residue. A portion was treated with silica-carbonate resin and used in the following step without further purification. ES/MS calcd. for C33H32N5O5S+ 610.2. Found m/z=610.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(C1C=C(S(O)=O)C=CC=1)(O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([OH:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(O)c1cccc(S(=O)O)c1
Product: COc1ccc(S(=O)O)cc1

Procedure:
The starting material, p-methoxybenzenesulfinic acid was prepared from p-methoxybenzenesulfonyl chloride by a procedure similar to that described in the literature for m-carboxybenzenesulfinic acid (see Davis and Smiles) J. Chem. Soc. 97, 1274 (1910). The crude acid so obtained (30.7 g) was added to a solvent mixture consisting of 200 ml of water and 100 ml of dioxane. The pH was adjusted to ca 8.0 with dilute sodium hydroxide solution and 21.0 g of sodium bicarbonate was added. The mixture was stirred, heated to 60° C. and 20.0 g (0.1 mole) of p-methoxybenzenesulfonyl chloride was added slowly over a 2 hour period, while maintaining the reaction mixture at about 60° C. After stirring for an additional hour, 200 ml of cold water was added. The crude solid product was recovered by filtration. On drying, 8.4 g (24% crude yield) of product with m.p. 173°-174° C. was obtained; this product was crystallized from acetic acid, giving 7.5 g (22% yield) of white solid melting at 190°-191° C. with decomposition.
Reaction SMILES: [C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)([OH:3])=[O:2].CO.[CH3:27]CN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:2][C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)=[O:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6α-carboxyandrostane-3,17-dione (Prepn. 16, 680 mg) in CH2Cl2 (30 mL) at 0° C., MeOH (160 μL), DMAP (20 mg) and EDAC (800 mg) were added. After stirring overnight at room temperature, H2O was added and the mixture was extracted with CH2Cl2 (2×). The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 60/40) to give the title compound II-ag (500 mg, 70%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.59 (3H, s), 2.53-0.75 (21H, m), 1.02 (3H, s), 0.79 (3H, s).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O1CCOCC1.[I-].[K+]>[OH:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: OCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A suspension of 4-phenylpiperidine (3.00 g, 18.6 mmol, 1.00 equiv), 3-bromopropan-1-ol (2.12 mL, 22.3 mmol, 1.20 equiv), potassium carbonate (12.8 g, 93.0 mmol, 5.00 equiv), and potassium iodide (124 mg, 0.74 mmol, 0.04 equiv) in n-butanol (50 mL) and 1,4-dioxane (50 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added and the mixture was extracted with CH2Cl2 (4×100 mL). The combined organic solutions were dried over MgSo4 and concentrated. The residue was crystallized from ethyl acetate to give 3.36 g (82%) of tan solid, which was characterized spectroscopically.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH:26](=[N:28][OH:29])[CH3:27].N#N>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.S([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>[F:6][C:7]([F:16])([F:15])[C:8]1[CH:9]=[C:10]([C:26](=[N:28][OH:29])[CH3:27])[CH:12]=[CH:13][CH:14]=1
Reactant: CC=NO
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=NO)c1cccc(C(F)(F)F)c1
Temperature: 65 °C
Yield: 84.3 %

Procedure:
To a three-neck indented, Morton style flask equipped with a sidearm for thermometer charged with 80 mL (240 mmol) of 3N sulfuric acid was added 10 mL (80 mmol) of 3-(trifluoromethyl)aniline (Aldrich Chemical Co.). The resulting suspension turned into a clear solution upon heating to 65° C. The solution was stirred vigorously and cooled to -5° C. using an acetone/ice bath to give a slurry. To the slurry was added a solution of 5.85 g (84.8 mmol) of sodium nitrite in 25 mL of water. The rate of addition was carefully adjusted so the internal reaction temperature was maintained between -5 and 0° C. The mixture was stirred at that temperature for 30 min. The diazonium thus obtained appears as a thin slurry. The slurry thickened when a solution of 20 g (244 mmol) of sodium acetate in 50 mL of water was added. Meanwhile, in another flask, 19 mL (320 mmol) of acetaldoxime, 1.50 g (8 mmol) of copper (II) acetate, 0.5 g (4 mmol) of sodium sulfite, and 20 g (244 mmol) of sodium acetate were combined and cooled to about 10° C. To this solution was added via a cannula or additional funnel the diazonium mixture. Immediate gas (N2) evolution was observed, and a two phase mixture (dark green oil and aqueous) was obtained. The mixture was stirred for 30 min before the reaction was worked up. To the mixture was added about 300 mL of toluene and the organic phase separated from the aqueous. The aqueous phase was extracted with another 100 mL of toluene. The combined toluene extracts (greenish color) were washed with 15% ammonium hydroxide solution (5×20 mL). Analysis using copper test strips from EM Science indicated the copper (I/II) content to be less than 10 ppm as compared to greater than 100 ppm before the ammonium hydroxide wash. The organic phase (orange color) was washed with 20 mL of brine and dried over magnesium sulfate. Removal of volatiles on the rotovap gave an orange oil which turned into a semi-solid upon fuirther drying on the vacuum pump to give 13.7 g (84%) of a solid product. In the analytical assay, it was found to contain 58.9% of the desired oxime product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([OH:37])=O)([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:75][S:76]([CH:79]5[CH2:81][CH2:80]5)(=[O:78])=[O:77])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:75][S:76]([CH:79]4[CH2:81][CH2:80]4)(=[O:78])=[O:77])=[O:37])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1

Procedure:
The title compound (11) was prepared from 17-[8-chloro-2-ethoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (10) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=659 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[N:21][C:22]=3[C:23]([O:38]C(C3C=CC=CC=3)C3C=CC=CC=3)=[C:24]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:25]=23)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:27]2[C:28](=[O:29])[C:24]3[C:23]([OH:38])=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[N:21]4)=[C:16]([C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[C:25]=3[CH2:26]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(c(C(=O)N3CCNCC3)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 445.8 %

Procedure:
Carboxamide 229 (0.0108 g, 0.0153 mmol) was dissolved in 1 mL of dichloromethane. To this was added 0.4 mL of triethylsilane and 0.2 mL of trifluoroacetic acid. Stirred at room temperature and after ten minutes complete by TLC. Concentrated off volatiles, azeotroped with toluene to give crude. Then dissolved in 0.6 mL dichloromethane, 0.6 ml trifluoroacetic acid. Stirred at room temperature for one hour. Concentrated off volatiles, azeotroped with toluene to give crude. Triturated twice with 1:1 diethyl ether/hexanes to give 7-(4-fluoro-benzyl)-9-hydroxy-5-(piperazine-1-carbonyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 230 (0.039 g, 0.0682 mmol, 100%.) 1H NMR (CD3SOCD3) δ 98.97 (s, 2H), 8.32 (d, 1H), 7.74 (s, 1H), 7.36 (dd, 2H), 7.19 (dd, 2H), 4.86 (d, 1H), 4.58 (d, 1H), 4.42 (d, 1H), 4.34 (d, 1H), 3.9-2.90 (m, 8H.) 19F NMR: −74.202 MS: 421 (M+1), 419 (M−1)
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].OS(O)(=O)=O.CCN(CC)CC.[CH3:30][C:31]([CH3:33])=O>>[CH3:30][C:31]1([CH3:33])[O:3][C@@H:2]2[C@@H:4]([C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]2[N:10]2[C:11](=[O:12])[NH:13][C:14](=[O:15])[CH:16]=[CH:17]2)[O:5]1
Reactant: CC(C)=O
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc(=O)[nH]c1=O

Procedure:
5′-O-(t-Butyldimethylsilyl)-2′,3′-O-isopropylidene uridine. A stirred suspension of uridine (1 g, 4.1 mmol) in anhydrous acetone (50 mL) was treated with H2SO4 (0.5 mL) drop wise at room temperature and the resulting mixture was stirred for an additional hour. The reaction was then neutralized with Et3N and was concentrated. The crude mixture was purified by column chromatography (5-8% MeOH:CHCl3) to afford 2′,3′-O-isopropylidene uridine (1.15 g, quant.) as a white solid. 1H NMR (CDCl3) d ppm 1.36 (s, 3H, —CH3), 1.57 (s, 3H, —CH3), 3.80 (dd, 1H, H-5′), 3.91 (dd, 1H, H-5″), 4.26-4.30 (m, 1H, H-4′), 4.95 (dd, 1H, H-3′), 5.02 (dd, 1H, H-2′) 5.56 (d, 1H, H-1′), 5.72 (d, 1H, H-5), 7.36 (d, 1H, H-6).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33](O)=[O:34])([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:39])=[N:3]1.[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH2:45])[CH3:41].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH:45][C:33]([C:32]1[CH:31]=[C:30]([S:27]([CH3:29])(=[O:28])=[N:26][C:24](=[O:25])[C:20]2[CH:19]=[C:18]([C:17]#[C:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:39])[CH:5]=4)=[O:8])[CH:11]=3)[CH:23]=[N:22][CH:21]=2)[CH:38]=[CH:37][CH:36]=1)=[O:34])[CH3:41]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(C(=O)O)c4)c3)c2)n(C)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoic acid (52 mg, 0.096 mmol), 2-diethylaminoethylamine (0.016 ml, 0.115 mmol), and N,N-diisopropylethylamine (0.034 ml, 0.192 mmol) in 3.0 ml DMF at room temperature was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (47 mg, 0.106 mmol). The reaction was stirred at room temperature for 1.5 hours, and then partitioned between EtOAc and dilute brine. The EtOAc layer was washed with saturated NaHCO3 solution, dilute brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow oil (combined 7 mg impure product from another lot) was chromatographed eluting with EtOAc/MeOH, then rechromatographed using a preparative TLC plate (eluted with (1:1:2.5) CHCl3:EtOAc:MeOH plus NH4OH) to give the title compound as a white solid foam (28 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]3=[O:26])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[C:27]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[C:15](=[O:26])[CH:16]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3cc(OC)ccc23)C1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3cc(OC)ccc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 14 g of the product of Step C, 8.2 ml of triethylamine and 4.5 ml of benzoyl chloride were reacted to obtain 18 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) (under an atmosphere of nitrogen for 10 minutes) was added 2,3-dimethylaniline (0.73 g, 0.00602 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) portionwise with stirring. The stirring was continued at ambient temperature for a further 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to as afford a transparent viscous liquid which was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to afford 1.5 g (98%) of 4-(2,3-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.0 (t, 1H), 6.6 (m, 2H), 4.1 (m, 2H), 3.5 (m, 1H), 3.0-2.9 (t, 2H), 2.3 (s, 3H), 2.1 (m, 2H), 2.0 (s, 3H), 1.5 (s, 9H), 1.4 (m, 2H). A solution of 4-(2,3-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.45 g, 0.00476 mole) in ethyl acetate.HCl (15 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 1.1 g (83) of (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 95.98%, 1H NMR (DMSO-d6): δ 9.4 (d, 1H), 9.0 (d, 1H), 7.3 (m, 3H), 3.7 (m, 2H), 3.3 (d, 2H), 3.1 (bs, 1H), 2.9 (m, 2H), 2.3 (d, 6H), 2.1 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[H-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18]([N:7]1[C:8]2[C:4](=[C:3]([N+:12]([O-:14])=[O:13])[C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:11])=[O:19]
Reactant: COC(=O)Cl
Reactant: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)n1c(C)cc2c([N+](=O)[O-])c(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-methyl-4-nitro-1H-indole (1.62 g, 7.69 mmol) is dissolved under an atmosphere of argon in dry DMF (30 ml). After addition of a NaH suspension (60% in mineral oil, 369 mg, 9.22 mmol) the mixture is stirred for 1 hour at RT. Methyl chloroformate (0.72 ml, 9.22 mmol) is added slowly during 10 minutes, and the reaction mixture is stirred at RT for 1 hour to form a yellowish suspension. After filtration and drying, the title compound is obtained in pure form. 1H NMR (DMSO, 400 MHz) δ 2.53 (s, 3H), 4.06 (s, 3H), 6.71 (s, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.30 (d, J=9.0 Hz, 1H); ES-MS: 268 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:26]=[CH2:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=CC(C([C@@H]2OC[C@H](NCC3C=CC(F)=CC=3)C(O)C2)C2C=CC=CC=2)=CC=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:26][CH3:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1nc(C(=O)OCCCC)c(O)c2ccc(Oc3ccccc3)cc12
Agent: OC1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccc(F)cc1
Product: CCCCOC(=O)c1nc(CC)c2cc(Oc3ccccc3)ccc2c1O

Procedure:
Synthesized from 4-Hydroxy-7-phenoxy-1-vinyl-isoquinoline-3-carboxylic acid butyl ester in analogy to example D-153 b); MS-(+)-ion M+1=366.1.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:14])[CH2:12]Br>>[CH3:9][O:10][C:11](=[O:14])[CH2:12][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COC(=O)CBr
Product: COC(=O)Cn1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with bromo-acetic acid methyl ester to provide the title compound: 1H NMR (400 MHz) 3.82 (s, 1H), 4.80, (s, 2H), 7.47 (d, 1H, J=1.7 Hz), 7.84 (d, 1H, J=1.7 Hz); gc/ms m/z 185 (M).
Reaction SMILES: C(C1C(=O)O[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]=2)(=O)C.[CH3:20][C:21]([C:23]1[C:32](=[O:33])[O:31][C:30]2[C:25](=[CH:26][C:27]3[CH2:40][CH2:39][CH2:38][N:37]4[C:28]=3[C:29]=2[CH2:34][CH2:35][CH2:36]4)[CH:24]=1)=[O:22]>C(O)C>[CH2:17]([N:14]([CH2:15][CH2:16][N:37]1[CH2:28][CH2:29][CH2:34][CH2:35][CH2:36]1)[C:9]1[CH:8]=[CH:7][C:12]([CH:13]=[CH:20][C:21]([C:23]2[C:32](=[O:33])[O:31][C:30]3[C:25](=[CH:26][C:27]4[CH2:40][CH2:39][CH2:38][N:37]5[C:28]=4[C:29]=3[CH2:34][CH2:35][CH2:36]5)[CH:24]=2)=[O:22])=[CH:11][CH:10]=1)[CH3:18]
Reactant: CC(=O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Reactant: CCN(CC)c1ccc2cc(C(C)=O)c(=O)oc2c1
Solvent: CCO
Product: CCN(CCN1CCCCC1)c1ccc(C=CC(=O)c2cc3cc4c5c(c3oc2=O)CCCN5CCC4)cc1

Procedure:
10-(3-(N-ethyl-N-(2-piperidinoethyl)-4-aminophenyl)propenoyl)-1H,2H,3H,5H,6H,7H,11H-[1]benzopyrano[6,7,8-ij]quinolizin-11-one (9) was prepared according to the procedure of Example 4 wherein 3-acetyl-7-diethylaminocoumarin was replaced by Coumarin 334 (Eastman Kodak, Rochester, N.Y.); λmax (ethanol)=503 nm ##STR14##
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][C:18]=1[O:29][CH:30]([CH3:32])[CH3:31].[Li]CCCC.CCCCCC>C1COCC1>[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:22])=[CH:19][C:18]=1[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: CON(C)C(=O)c1ccc(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -76 °C
Reaction time: 1.5 h

Procedure:
A 3-liter four neck round-bottomed flask (flame dried) was charged 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (72.88 g, 0.25 mol), 4-fluoro-3-isopropoxy-N-methoxy-N-methylbenzamide (60.39 g, 0.25 mol) and dry THF (700 mL) under N2. The solution was cooled to −76° C., and a solution of n-BuLi in hexane (2.5M, 100 mL, 0.25 mol) was drop-wise maintaining the reaction mixture temperature below −70° C. over a period of 40 min. The reaction mixture was stirred at −76° C. for 1.5 h then quenched with 1N HCl (500 mL). The mixture was concentrated in vacuo to half the volume and was partitioned between EtOAc and H2O (v/v 1:0.3, 1 L). The organic phase was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic extracts were washed with brine and then concentrated in vacuo to give a yellow oil which was purified by column chromatography using CH2Cl2 in hexanes (0% to 20%) to give (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone as a colorless oil contaminated with a by-product (49.0 g, 50%). LC-MS (10-90% MeOH in H2O with 0.1% TFA in a 2-min gradient) 393.2 (M+H), retention time=2.15 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:13][NH:14][C:15]([C:17]2[CH:25]=[CH:24][C:20]3[N:21]=[CH:22][S:23][C:19]=3[CH:18]=2)=O)=[O:12])[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[O:12][C:15]([C:17]3[CH:25]=[CH:24][C:20]4[N:21]=[CH:22][S:23][C:19]=4[CH:18]=3)=[N:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CCc1cccc(C(F)(F)F)c1)NNC(=O)c1ccc2ncsc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc(CCc2nnc(-c3ccc4ncsc4c3)o2)c1
Yield: 74.6 %

Procedure:
A solution of N′-[3-[3-(trifluoromethyl)phenyl]propionyl]benzothiazole-6-carbohydrazide (433 mg, 1.10 mmol) and p-toluenesulfonyl chloride (419 mg, 2.20 mmol) in pyridine (5 mL) was stirred under an argon atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 0.1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (308 mg, yield 75%) as colorless crystals.