Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][N:13]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][C:30]3=[O:41])[CH2:23][CH2:22]2)C(=O)OC(C)(C)C)=[N:10][C:9]2[N:8]([CH3:42])[C:7](=[O:43])[CH2:6][S:5][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][NH:13][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][C:30]3=[O:41])[CH2:23][CH2:22]2)=[N:10][C:9]2[N:8]([CH3:42])[C:7](=[O:43])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4nc5c(cc4Cl)SCC(=O)N5C)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4nc5c(cc4Cl)SCC(=O)N5C)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To 20 mL of a chloroform solution containing 0.23 g of tert-butyl (7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.16 g of 1-(2-(4-((7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:31][CH2:32][CH3:33])[C:24]=1[C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1)[C:19](O)=[O:20])[CH3:14].Cl.Cl.[O:36]=[C:37]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([C:52]3[CH:53]=[C:54]([C:58]([OH:60])=[O:59])[CH:55]=[N:56][CH:57]=3)[CH:50]=2)[O:45][C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38]1.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C:19]([N:42]2[CH2:41][CH2:40][C:39]3([CH2:38][C:37](=[O:36])[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([C:52]5[CH:53]=[C:54]([C:58]([OH:60])=[O:59])[CH:55]=[N:56][CH:57]=5)[CH:50]=4)[O:45]3)[CH2:44][CH2:43]2)=[O:20])[CH:22]=[C:23]([O:31][CH2:32][CH3:33])[C:24]=1[C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1)[CH3:14]
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (130 mg) and triethylamine (0.446 mL) were added to a DMF solution (4 mL) of 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (232 mg), and stirred at 70° C. for 2 hours. To the reaction liquid, added was a DMF suspension (2 ml) of 5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-3-carboxylic acid dihydrochloride (370 mg) and triethylamine (0.335 ml) that had been prepared separately, and further stirred at that temperature for 1 hour. 1 N hydrochloric acid and water were added to the reaction liquid, the resulting solid was taken out through filtration, and recrystallized from methanol to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1C=CC=CC=1.[CH3:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:53]3[CH2:54][CH2:55][CH2:56][N:50]([CH3:49])[CH2:51][CH2:52]3)=[O:17])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN1CCCNCC1
Reactant: O=C(O)CC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3[N+](=O)[O-])CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 0.350 g (1.02 mmol) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid in dimethylformamide (5 mL) is added 0.450 g (1.19 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate followed by 0.380 mL (2.13 mmol) of pyridine. The mixture is stirred at room temperature for 1 hour then 0.225 mg (1.97 mmol) of N-methylhomopiperizine is added and the mixture is stirred at room temperature for 1 h. The mixture is diluted with water and extracted with ethyl acetate. The combined organic phase is washed with water followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.310 g (69.2%) of 2-(5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-1-(4-methyl-[1,4]diazepan-1-yl)-ethanone as an orange oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:34])([F:36])[F:35])=[CH:17][N:16]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2-(2-(2-(2-((4-(Piperazin-1-ylmethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (25) (11 mg, 0.022 mmol) was dissolved in methanol (1 mL). 37% Formaldehyde solution (7 μL) was added followed by sodium triacetoxyborohydride (24 mg, 0.11 mmol). The mixture was stirred vigorously at room temperature for two hours then concentrated. The residue was suspended in 10% sodium hydroxide (1 mL) and brine (2 mL) then extracted with ethyl acetate (5×2 mL). The combined ethyl acetate phases were washed with brine, dried over sodium sulfate, evaporated and the residue evaporated from DCM to give the title compound (36) (10.3 mg, 94% yield) as an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.46 (d, J=0.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.18-7.13 (m, 1H), 7.13-7.07 (m, 3H), 3.57 (s, 2H), 3.46 (s, 2H), 3.06 (qd, J=6.8, 3.1 Hz, 2H), 3.01-2.94 (m, 2H), 2.54 (s, 8H), 2.29 (s, 3H). LCMS Method C: 4.70 min; m/z 513.2 [M+H+]+; m/z 511.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([Cl:9])[C:6]=1[C:7]#[N:8].OC1C=CSC=1.P(Cl)(Cl)(Cl)=O.OC1SC=CC=1.[CH3:29][N:30]([CH3:33])[CH:31]=O>>[Cl:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([N:1]=[CH:29][N:30]([CH3:33])[CH3:31])[S:3][C:4]=1[CH:10]=[O:11]
Reactant: CN(C)C=O
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: Oc1cccs1
Agent: Oc1ccsc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N

Procedure:
The intermediate N'-(4-chloro-3-cyano-5-formyl-2-thienyl)-N,N-dimethylformamidine (IV) ##STR4## is formed from the 4-hydroxythiophene derivative (III) by treatment with a mixture of N,N-dimethylformamide and phosphoryl chloride and then converted direct to 2-amino-4-chloro-3-cyano-5-formylthiophene by acid hydrolysis, without its having been isolated. For this it is expedient to dissolve the 4-hydroxythiophene derivative (III) in N,N-dimethylformamide and add phosphoryl chloride to the solution at a temperature of from 20° C. to 80° C.; the mole ratio of the hydroxythiophene to N,N-dimethylformamide to phosphoryl chloride is generally from 1:10:2 to 1:20:3. After a further period of from 2 h to 8 h, during which the solution is kept stirred at a temperature of from 20° C. to 80° C., the formamidine (IV) that is formed is subjected to acid hydrolysis, which is done conveniently by running the reaction mixture into water. After completion of the latter procedure (which is accompanied by a strongly exothermic reaction) the mixture is usually stirred at a temperature of from 80° C. to 100° C. for from 1 h to 4 h, during which time the required thiophene derivative (II) precipitates. The product is finally separated, washed, and dried.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([OH:20])[C:6](=[O:19])[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1>ClCCl>[CH3:23][C:24]1[CH:6]=[C:7]([C:2]([O:19][C:6]2[C:5](=[O:20])[CH:4]=[C:3]([O:21][C:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH3:37])[CH:29]=3)=[O:35])[C:2](=[O:1])[C:7]=2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCC1=C(O)C(=O)C=C(O)C1=O
Solvent: ClCCl
Product: CCCCCCCCCCCC1=C(OC(=O)c2cccc(C)c2)C(=O)C=C(OC(=O)c2cccc(C)c2)C1=O
Reaction time: 3 h

Procedure:
To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.5 g, 1.7 mmole) in dichloromethane (20 mL) was added pyridine (0.55 mL, 6.8 mmole). To this, was added 3-toluoyl chloride (0.654 gm, 4.25 mmole) at 15-20° C. and stirred, allowed to attain 30° C. and stirring was continued for 3 h (TLC). The organic layer was extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to crude which was purified by SiO2 column chromatography (10-20% EtOAc in hexane) to pure mass (0.64 g, 71%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[OH:7][CH:8]([CH2:20][OH:21])[CH2:9][N:10]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH2:11][CH2:12][CH2:13][CH3:14]>>[Cl-:1].[CH2:11]([N+:10]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])([CH2:9][CH:8]([OH:7])[CH2:20][OH:21])[CH2:2][CH:3]([OH:6])[CH2:4][OH:5])[CH2:12][CH2:13][CH3:14]
Reactant: OCC(O)CCl
Reactant: CCCCN(CC(O)CO)CC(O)CO
Product: CCCC[N+](CC(O)CO)(CC(O)CO)CC(O)CO
Product: [Cl-]
Reaction time: 26 h

Procedure:
A fresh quantity of 66.3 g (0.6 mole) of 1-chloro-2,3-propanediol was added to the unpurified bis(2,3-dihydroxypropyl)-n-butylamine. These reagents were then brought to a temperature of 100° C. for 26 hours. Separation of the ammonium salt form was carried out in a methanolic medium with the aid of a cation exchange resin (Bio-Rad AG 50W-X8). In this way, 21.9 g of n-butyl-tris(2,3-dihydroxypropyl)ammonium chloride were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:15].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]2[CH:12]([O:13][CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:15])[CH2:29][CH2:28]1
Reactant: COC1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1c2ccccc2C(=O)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 10 h
Yield: 21.4 %

Procedure:
The procedure is as in Example 25, starting with (RS)-2-(2-bromoethyl)-3-methoxyisoindolinone (2.4 g), 4-[(5-fluoro-3-indolyl)methyl]piperidine (2.1 g) and sodium bicarbonate (0.74 g) in a mixture of dimethylformamide (50 cc) and tetrahydrofuran (40 cc). The mixture is heated to boiling for 10 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with ethyl acetate as eluent, and recrystallization a first time in acetonitrile (40 cc) and then in methyl ethyl ketone (35 cc), (RS)-2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-3-methoxyisoindolinone (0.8 g), m.p. 175° C., is obtained.
Reaction SMILES: [C:1]([C:9]1([CH3:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([CH3:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
tert-Butyl 3-benzoyl-3-methylpiperidine-1-carboxylate (278 mg, 0.92 mmol) was dissolved in 1:1 THF/MeOH (8 mL) and NaBH4 (70 mg, 1.84 mmol, 2 equiv) was added. After stirring 30 min at rt, LC-MS showed the reaction was complete. After concentration, the residue was partitioned between ether and diluted (˜1%) aq HCl. The aqueous layer was separated and extracted twice with ether. The combined organic layers were washed with satd aq NaHCO3, brine, dried over Na2SO4 and evaporated to afford crude product which was purified by chromatography on a 12-g prepacked silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford tert-butyl 3-(hydroxy(phenyl)methyl)-3-methylpiperidine-1-carboxylate (198 mg, 71%). LC-MS (3 min) tR=1.83 min, m/z 328 (M+Na).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>C1COCC1>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
To 1.35 g (6.12 mmol) of 2-chloro-5-fluoro-1,3-dinitrobenzene in 20 mL of THF at 0° C. was added 6.1 mL (12 mmol) of 2N methylamine in THF. The cold bath was removed and the reaction was stirred at room temperature for 45 minutes. The solution was concentrated, diluted with ether and washed with saturated sodium bicarbonate solution. The resulting organic solution was dried over sodium sulfate, filtered and concentrated giving 1.30 g (99%) of the title compound as a bright orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[C:21]1[CH:28]=[N:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:23]([C:22]1[CH:21]=[CH:28][N:27]=[CH:26][C:25]=1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1)=[O:24]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Reactant: O=Cc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnccc2C=O)ccc1C#N
Yield: 71.4 %

Procedure:
A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (259 mg, 1 mmol), 3-bromoisonicotinaldehyde (186 mg, 1.000 mmol), a solution of sodium carbonate (2M in water, 1.000 ml, 2.000 mmol), bis(triphenylphosphine)palladium(11) chloride (17.55 mg, 0.025 mmol) in DMF (6 mL, dry) was heated to 120° C. for 3 hrs. After concentration, the residue was dissolved into CH2Cl2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH—CH2Cl2, v/v, 0.5%-1%) yielded colorless solid (170 mg). 1H NMR (400.3 MHz, CDCl3): δ 3.99 (s, 3H), 6.98 (d, J=1.32 Hz, 1H), 7.05 (dd, J=1.48, 7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.81 (d, J=5 Hz, 1H), 8.81 (s, 1H), 8.90 (d, J=5 Hz, 1H), 10.04 (s, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[BH3-][C:10]#[N:11].[Na+].C=O.[C:15](O)(=O)C>C(#N)C.O>[CH3:15][N:11]([CH3:10])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccnc(N)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccnc(N(C)C)c1

Procedure:
To a mixture of 2-amino-4-picoline (33 g), NaBH3CN (57 g), formaldehyde (37% aq. solution, 240 mL) in acetonitrile (1 L) and water (200 mL) was added dropwise acetic acid (60 mL) at 0° C. in 2 hr. The resultant solution was stirred at RT for 7 days and then concentrated in vacuo. The residue was basified with solid NaOH to pH 10 and extracted with hexanes (3×700 mL). The combined extract was washed with 1N aq. NaOH and brine, dried over Na2SO4 and evaporated in vacuo to give 2-dimethylamino-4-methylpyridine as a colorless oil (Cmpd 1a, 36 g, 88%). 1H NMR (CDCl3): 2.26 (s, 3H), 3.07 (s, 6H), 6.33 (s, 1H), 6.40 (d, 1H), 8.02 (d, 1H); MS (CI) m/e 137 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]#[CH:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>C(Cl)Cl>[C:1]([NH:8][C@H:9]([C:12]#[CH:13])[CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of (R)-N-Boc-2-amino-but-3-yn-1-ol (150 mg, 0.81 mmol) (Example 104B) and imidazole (110 mg, 1.62 mmol) (Aldrich) in CH2Cl2 (10 mL) was added at 0° C. tert-butyldimethylsilyl chloride (146 mg, 0.97 mmol) (Fluka). After 5 min the reaction mixture was poured into H2O and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated to a residue which after silica gel column chromatography with a 0-30% Et2O in hexanes gradient afforded the product. (Yield 210 mg, 83%).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:36])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[C:16]([CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+].O>CO>[CH3:11][CH:8]1[CH2:7][CH2:6][C:5]([NH:12][C:13](=[O:36])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[C:16]([CH:30]([OH:35])[C:31]([F:32])([F:33])[F:34])[CH:15]=2)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]1
Reactant: COC(=O)C1(NC(=O)c2ccc(OCCc3cccc(C)c3)c(C(O)C(F)(F)F)c2)CCC(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(CCOc2ccc(C(=O)NC3(C(=O)O)CCC(C)CC3)cc2C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
170 mg of 4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]-cyclohexanecarboxylic acid methyl ester and 28 mg of lithium hydroxide were stirred in 50 ml of methanol and 1 ml of water for 5 h at 40° C. The reaction mixture was then diluted using 10 ml of water, the methanol evaporated and acidified to pH=2 using aqueous NaHSO4-solution. The mixture was then stirred for 30 minutes at room temperature, the product isolated by filtration and dried in vacuo to yield 138 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 69.1 %

Procedure:
tert-Butyl 3-(2-cyano-4-pyridyl)propionate (0.51 g, 2.2 mmol) and methyl thiosalicylate (0.55 g, 3.3 mmol) were dissolved in toluene (2 ml), and triethylamine (0.47 ml, 3.4 mmol) was added thereto. The mixture was refluxed for 8 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.56 g, 69%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[Cl:10].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:10][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Cl)c(F)c1F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)c(F)c1Cl

Procedure:
If 0.15 mol of 2,3,4-trifluorochlorobenzene in 50 g of 100% strength sulfuric acid as diluent is used and nitration is carried out with 30.5 g (0.165 mol) of mixed acid prepared from 68.8% by weight of 100% strength H2SO4 and 31.2% by weight of 100% strength HNO3 at from 5° to 12° C., then reaction is complete after metered addition for 1 hour followed by stirring for an additional hour. The result is essentially the same.
Reaction SMILES: Cl[CH:2]([C:6]1[CH:21]=[CH:20][C:9]2[O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4].[H][H]>[C].[Pd].C(OCC)(=O)C>[O:15]=[C:14]1[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][O:10][C:9]2[CH:20]=[CH:21][C:6]([CH2:2][C:3]([OH:5])=[O:4])=[CH:7][C:8]1=2
Reactant: [H][H]
Reactant: O=C1c2ccccc2COc2ccc(C(Cl)C(=O)O)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 4 h

Procedure:
A mixture containing 6,11-dihydro-α-chloro-11-oxodibenz[b,e]oxepin-2-acetic acid in the amount of 0.2 grams, 0.2 grams of 5% palladium-carbon reduction catalyst, 30 ml ethyl acetate and commercially available 4Å molecular sieve (Davidson Grade 514, Type 4A, 8-12 mesh beads, alumina silicate base with sodium cation, available from W. R. Grace) was treated with hydrogen (10 psi). The reduction reaction was run for 4 hours and then worked up by filtration and concentration in vacuo to yield 0.18 grams of crude product. 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (V) was obtained after purification by chromatography on silica gel using ethyl acetate. Its structure was confirmed by comparison of its infra-red, proton-NMR and thin layer chromatography with that of an authentic sample.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH3:27])=[C:18]3[CH:25]([NH2:26])[CH2:24][CH2:23][CH2:22][N:19]32)=[CH:15][CH:14]=1.O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH3:27])=[C:18]3[CH:25]([NH:26][CH:1]=[O:3])[CH2:24][CH2:23][CH2:22][N:19]32)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(C)c3n(c2c1)CCCC3N
Reactant: O=CO
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(C)c3n(c2c1)CCCC3NC=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A mixture of formic acid (8.5 g,) and acetic anhydride (15.2 g) was heated to 60° C. for 4 hours, then cooled to 0° C. A solution of 6,7,8,9-tetrahydro-3-methoxy-10-methylpyrido[1,2-a]indol-9-amine (6.1 g, 26.6 mmol) in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours under exclusion of moisture. It was then poured into water (75 mL) and extracted with ether (3×100 mL). The combined organic layers were washed with 5% hydrochloric acid (50 mL), and then with saturated sodium bicarbonate (3×50 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 5.25 g (77%) of the title compound as an off white solid, m.p. 181°-182.5° C.