Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:19]([C:10]1[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[N:11]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCc1nc(N(C)C)nc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCc1nc(N(C)C)nc(C)c1O
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution containing 150 mg (0.48 mmol) 5-(benzyloxy)-4-decyl-N,N,6-trimethylpyrimidin-2-amine in 5 mL of methanol were added 5 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/E). The reaction mixture was stirred at 23° C. under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrated was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×3 cm). Elution with 4:1 hexane-ethyl acetate afforded the expected product as white solid: yield 33 mg (28%); mp: 71-72° C.; silica gel TLC Rf 0.25 (4:1 hexanes-ethyl acetate); 1H NMR (methanol-d4) δ 0.87 (t, 3H, J=6.8 Hz), 1.21-1.31 (m, 14H), 1.65 (quint, 2H, J=7.2 Hz), 2.26 (s, 3H), 2.62 (dd, 2H, J=7.2, 7.2 Hz) and 3.05 (s, 6H); 13C NMR (methanol-d4) δ 13.01, 17.55, 22.29, 27.27, 29.02, 29.15, 29.17, 29.26, 29.29, 31.24, 31.64, 36.52, 36.52, 138.04, 155.59, 157.31 and 159.41; mass spectrum (APCI), m/z 294.2554 (M+H)+ (C17H32N3O requires 294.2545).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:24])=O)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:47]([O:49][C:50](=[O:53])[CH2:51][NH2:52])[CH3:48]>CN(C)C=O.ClCCl>[CH2:47]([O:49][C:50](=[O:53])[CH2:51][NH:52][C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:24])[CH3:48]
Reactant: CCOC(=O)CN
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)c2n1CCOC2
Temperature: 40 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (50 mg, 0.168 mmol) in dimethylformamide (1.7 ml) was added 1-hydroxybenzotriazole (23 mg, 0.168 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.168 mmol). The mixture was stirred for 1 h at 40° C., then amino-acetic acid ethyl ester (17 mg, 0.168 mmol) was added and the mixture was stirred at 25° C. overnight. Excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The residue was dissolved in a small amount of acetonitrile, excess water was added and the solution was freeze-dried to give 52 mg (82%) of {[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-acetic acid ethyl ester. LC/MS (method 4): Rt=1.19 min; m/z=414.2 (M+H+). 1H-NMR: δ (ppm)=8.46 (1H, t), 8.21 (1H, d), 7.35-7.36 (3H, m), 7.30 (2H, t), 7.21 (1H, t), 4.91 (2H, dd), 4.82 (1H, q), 4.19 (2H, t), 4.11 (2H, q), 3.90-3.92 (4H, m), 1.71-1.83 (2H, m), 1.21 (3H, t), 0.88 (3H, t).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].[CH2:16]([OH:18])[CH3:17]>>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:18][CH2:16][CH3:17])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Into a 2-liter resin kettle, equipped with stirrer, reflux condenser and thermometer, was charged 632 g. ethanol. To the ethanol was added carefully, below 50° C., in 15-20 minutes, 42.0 g. sodium hydroxide. To this was added, in 15 to 20 minutes, 213 g. 2,4-dinitrochlorobenzene, with the temperature maintained below 50° C. The resulting mixture was heated to reflux and held at reflux for 3 hours to give an ethanol solution of 2,4-dinitrophenetole. After cooling to room temperature, the ethanolic reaction solution was treated with 340 g. iron powder and 200 ml. water, exhibiting a mild exotherm. A solution of 12 ml. hydrochloric acid, 12 ml. glacial acetic acid and 100 ml. water was added dropwise over 1 hour at a rate to maintain 62°-75° C. This reaction mass was refluxed under a nitrogen atmosphere for 3 hours, then cooled to 0° to 5° C., and assayed for 2,4-diaminophenetole by perchlorate titration. To the cooled reaction mass was added 80 g. sodium hydroxide (50% aqueous solution), and then an exact equivalent amount of acetic anhydride, about 90-94 g. acetic anhydride, depending on the perchlorate assay. The temperature was maintained at 0° to 5° C. during this addition. The acetic anhydride was added dropwise over a period of about 2.5 hours. Following the addition of the acetic anhydride, the pH was adjusted to 6.8-7.0. The reaction product was treated with 20 g. of activated charcoal and 10 g. of diatomaceous earth at 80° C. and filtered to clarify. The filter residue was washed three times with 50 ml. of hot 1:1 ethanol-water. The combined filtrate and washings was heated to distill off ethanol, until the pot temperature reached 98° C. The aqueous pot residue was cooled to 10°-15° C. and filtered to give substantially pure crystalline product, assayed at 126 g. of 3-amino-4-ethoxyacetanilide, 65-70% of theory, based on the 2,4-dinitrochlorobenzene starting material.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH2:6]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([C:19]1[C:7]2[CH2:6][C:5](=[CH:4][CH2:3][CH2:2][Br:1])[C:15]3[C:10]([O:9][C:8]=2[CH:16]=[CH:17][CH:18]=1)=[N:11][CH:12]=[CH:13][CH:14]=3)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: BrCCC=C1Cc2ccccc2Oc2ncccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cccc2c1CC(=CCCBr)c1cccnc1O2
Temperature: 0 °C

Procedure:
A dry 3 L three-necked, round-bottomed flask was fitted with a magnetic stirring bar, a glass stopper, a rubber septum, and an argon inlet. Under an argon atmosphere, 94.0 g. of 5-(3-Bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridine (0.30 mole) and 900 mL of dry dichloromethane were added to the flask and the flask was cooled with an ice bath. To the solution was slowly added 78.5 g. of aluminum chloride (0.83 mole), followed by 17.8 mL of acetyl chloride (0.25 mole), and the mixture was stirred for an hour at 0° C. The reaction mixture was poured to 1500 g of ice, and the layers were separated. The aqueous layer was extracted with three 400 mL portions of ethyl acetate. Dichloromethane layer and the organic extracts were combined and washed successively with 1 lL of saturated aqueous sodium bicarbonate and 1 L of saturated aqueous sodium chloride. The organic solution was dried with anhydrous magnesium sulfate, filtered, and evaporated (aspirator vacuum, ca. 30° C.). The oily residue was chromatographed on 800 g. of Silica gel 60 by eluting with 5:1-1:1 (v/v) hexane-ethyl acetate mixture. The elution was evaporated, giving the titled compound as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][C:16]([C:23]([OH:25])=[O:24])=[C:15]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1.O>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][C:16]([C:23]([O:25][CH2:7][CH3:8])=[O:24])=[C:15]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: COc1ccc(-c2c(C(=O)O)[nH]c3cc(OC)c(OC)cc23)cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Potassium carbonate (0.139 g) and ethyl iodide (0.13 ml) were added to a solution of 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (0.3 g) in N,N-dimethylformamide (5 ml). The mixture was stirred for 3 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give ethyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (0.272 g, 84%) as pale red prisms.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[NH:37][CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1.[C:48]([O:52][C:53]([N:55]1[CH2:58][CH:57]([C:59](O)=[O:60])[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[N:37]([C:59]([CH:57]4[CH2:58][N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]4)=[O:60])[CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC3CN(Cc4ccc(F)cc4)CCN3c3ncccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (94 mg, 0.465 mmol) in CH2Cl2 (2 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was applied directly to a column of silica gel and eluted with 5% methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])=[CH:5][CH:4]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([O:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COCC[C@H](O)CO)cc1
Solvent: c1ccncc1
Product: COc1ccc(COCC[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of Compound 4 (22.6 grams, 100 mmoles) in 200 ml dry pyridine, trityl chloride (30.7 grams, 110 mmoles) was added dropwise, under argon atmosphere and the mixture was stirred overnight at room temperature. The solvent was thereafter evaporated to dryness and the residue was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was thereafter removed under reduced pressure. The resulting yellowish oily residue was purified by silica gel chromatography, using 1:2 (v:v) ethyl acetate:hexane as eluent. 41.2 grams (88% yield) of Compound 5 were obtained as an oil.
Reaction SMILES: C([O-])=O.[NH4+].[NH2:5][C:6]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[C:20]([O:27]CC3C=CC=CC=3)[C:19]=2[CH3:35])=[O:17])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C=O)C.[Pd]>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[C:20]([OH:27])[C:19]=2[CH3:35])=[O:17])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OCc3ccccc3)c3ccccn23)ccc1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2c(C)c(O)c3ccccn23)ccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.365 mg (5.79 mmol) of ammonium formate and 0.102 g (0.1 mmol) of palladium-on-carbon (10%) are added, at ambient temperature under an inert atmosphere, to 0.8 g (1.93 mmol) of methyl 2-amino-5-{[1-(benzyloxy)-2-methylindolizin-3-yl]carbonyl}benzoate in 30 ml of DMF. The reaction medium is stirred for 3 hours at ambient temperature and then filtered. The palladium is rinsed with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. A green oil is obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: FC(F)(F)c1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2C(F)(F)F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-trifluoromethylphenylilithium (˜3 equiv, freshly prepared from 1-iodo-2-trifluoromethylbenzene as in Example 2A), to give (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-trifluoromethyl-phenyl)-methanone. MS (M+H)+: 328.
Reaction SMILES: [CH:1]([Si:4]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]3[CH:16]=[C:17]([O:20][C@H:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C@@H:24]([NH2:31])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)[CH2:7]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:31][C@@H:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([N:8]5[CH2:9][CH2:10][C@H:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:32]([CH3:34])[CH3:33])[CH:35]([CH3:37])[CH3:36])[CH2:7]5)=[N:12][N:13]=4)[CH:16]=3)[CH2:22][CH2:23]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Yield: 23 %

Procedure:
A solution of Intermediate 26c (70 mg, 0.134 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 81 mg, 0.201 mmol) and DIPEA (70 mg, 0.54 mmol) in DMF (2 mL) was stirred at 60° C. for 30 min. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as an off-white foam (19 mg, 23%). LCMS (Method 1): Rt 4.70, m/z 777 [MH+].
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[C:3]=1[CH3:24].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[C:3]=1[CH3:24]
Reactant: COC(=O)Cc1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(CC(=O)O)c(C)nc3sc(C)c(C)c23)cc1
Temperature: 60 °C
Yield: 36.3 %

Procedure:
To a solution of methyl 2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.049 g; 0.144 mmol) in dioxane (3.5 mL) and water (0.9 mL) was added a 1N lithium oxide solution (0.9 mL; 0.90 mmol). The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.017 g (37%) of the title compound as a white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH:18]=[C:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)[CH2:13]1)=O)C.[OH-].[Na+]>CCOCC>[CH3:10][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH:18]=[C:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)[CH2:13]1
Reactant: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
To a solution of lithium aluminum hydride (155 mg) in anhydrous ether was added a solution of 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene (600 mg) in anhydrous ether under ice-cooling, and the resulting mixture was stirred under ice-cooling for 1 hour and under reflux for 2.5 hours. The reaction mixture was cooled, admixed with 10% aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(4-methylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 243° - 244° C (decomp.) (oxalate).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](=[N:34]O)[NH2:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:22]3[O:23][N:34]=[C:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:33]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: NC(=NO)c1ccccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4F)no3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
73 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-carboxylic acid (Example 41A) and 47 mg (0.24 mmol, 1.1 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 46 mg (47% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:47]2[CH:48]=[CH:49][C:44]([C:41]3[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=3)=[CH:45][CH:46]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 4-bromobiphenyl according to the general procedure C. Obtained as a yellow solid (1.29 g).
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([NH2:10])=O)[CH2:4]1.C(N(CC)C(C)C)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[Cl:20][CH2:21][C:22]([N:6]1[CH2:7][C@@H:3]([F:2])[CH2:4][C@H:5]1[C:8]#[N:10])=[O:23]
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
A suspension of 1.4 g of (2S,4S)-4-fluoropyrrolidine-2-carboxamide monohydrochloride prepared according to the similar method as that described in a patent reference (International Publication WO02/38451 pamphlet), and 3.0 ml of N,N-diisopropylethylamine in 10 ml of chloroform was added dropwise to a solution of 0.73 ml of chloroacetyl chloride in 14 ml of chloroform under cooling with an ice-water bath, and the reaction mixture was stirred for 30 minutes under cooling with an ice-water bath. Then, the reaction mixture was concentrated under reduced pressure. To a solution of the resulting residue in 14 ml of chloroform, 2.4 ml of trifluoroacetic anhydride was added dropwise under cooling with an ice-water bath. Then, the reaction mixture was allowed to room temperature, and stirred for 1 hour. This was concentrated under reduced pressure, and 0.1 M hydrochloric acid was added to the resulting residue, and this was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform to chloroform/methanol=30/1) to obtain 0.84 g of (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[N-:11]=[N+:12]=[N-:13].[Na+].C(O)(=O)C.[OH-].[Na+]>CCOCC.C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7]2[NH:13][N:12]=[N:11][N:8]=2)[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCCCO
Product: Fc1ccc(Cl)cc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, Et2O (100 mL) and 10% aqueous NaOH (200 mL) were added sequentially. The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (−15° C.) and acidified to pH 1 with conc. HCl. A gray solid precipitated. The solid was dried in vacuum at 50° C. to give 1.76 g (49%) of 5-(5-chloro-2-fluoro-phenyl)-1H-tetrazole: mp partial melt at 110° C., complete melting at 124° C.);