Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12])=O)(C)(C)C>O1CCOCC1>[ClH:41].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][C:35]3[CH:36]=[C:37]([Cl:42])[CH:38]=[C:39]([Cl:41])[CH:40]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCC(Oc3cc(Cl)cc(Cl)c3)CC2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)N2CCC(Oc3cc(Cl)cc(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (13 mL) was added to a solution of 1-[trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl]-4-(3,5-dichlorophenoxy)piperidine (C, 640 mg) in 1,4-dioxane (13 mL) at room temperature. After stirring at room temperature for 30 min, the reaction mixture was evaporated in vacuo. The residue was washed with ether to give the titled compound (361 mg) as white crystals: 1H NMR (400 MHz, D2O) δ 1.80 (br s, 2H), 2.03 (br s, 2H), 2.40 (m, 1H), 2.61 (m, 1H), 3.46-3.50 (m, 2H), 3.60 (br s, 1H), 3.77 (m, 3H), 3.86 (s, 2H), 4.58 (br s, 1H), 4.72 (br s, 1H), 5.03 (t, J=8.3 Hz, 1H), 7.03 (br s, 2H), and 7.10 (br s, 1H); mass spectrum (EI+) m/e 415.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:12][C:13]2[S:14][C:15]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][C:17]=2[C:18]([NH2:20])=[O:19])=[N:7][CH:6]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccc(Br)nc1
Reactant: NC(=O)c1cc(-c2ccccc2)sc1N
Product: CC(C)(O)c1ccc(Nc2sc(-c3ccccc3)cc2C(N)=O)nc1

Procedure:
2-{[5-(1-Hydroxy-1-methylethyl)pyridin-2-yl]amino}-5-phenylthiophene-3-carboxamide was prepared using 2-(6-bromopyridin-3-yl)propan-2-ol (79.3 mg, 0.367 mmol) (for preparation, see WO 2004/050024 A2 Example 120 Step A) and 2-amino-5-phenylthiophene-3-carboxamide (80 mg, 0.367 mmol) as the starting materials according the general procedure in Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:16]=[CH:15][C:14]3[CH:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=O)[NH:10][C:9]=3[N:8]2[N:24]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:27])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:27][C:11]1[N:10]=[C:9]2[C:14]([CH:15]=[N:16][C:7]3[N:8]2[N:24]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a 100 mL three necked round bottom flask was added 2-tert-butyl-7-phenyl-9H-1,4,9,9b-tetraaza-cyclopenta[a]naphthalen-8-one (1 g, 3.14 mmol, 1.00 equiv), CHCl3 (20 mL), thionyl chloride (0.94 mL, 4.00 equiv) and DMF (48 μL, 0.20 equiv) and the resulting solution was stirred for 1 h at 70° C. under nitrogen. After 1 h, additional thionyl chloride (0.47 mL, 2.00 equiv) and DMF (48 μL, 0.20 equiv) was added and the resulting solution was stirred for an additional 2 h at 70° C. After a total of 3 h, the resulting mixture was concentrated under vacuum and the pH value of the solution was adjusted to 7 with saturated aqueous NaHCO3 solution. The resulting solution was extracted with ethyl acetate and the organic layers were combined and dried and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether as the eluent to give the Compound [CCXXXIX] as a yellow solid. 1H NMR (300 MHz, DMSO, δ, ppm) 9.09 (s, 1H), 8.74 (s, 1H), 7.60-7.52 (m, 5H), 6.97 (s, 1H), 1.44 (s, 91-1); LC-MS: m/z=337 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:35])[CH:32]=2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][C:31]4[CH:32]=[C:33]5[C:28](=[CH:29][CH:30]=4)[CH2:27][N:26]([CH3:25])[CH2:34]5)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1Cc2ccc(N)cc2C1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2C1

Procedure:
166 f) N-Methyl-N-(3-{[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (34.0 mg, 0.229 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as tan foam (0.048 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=3.6 Hz, 1H), 7.87-7.81 (m, 2H), 7.53 (s, 1H), 7.33-7.25 (m, 2H), 7.14 (d, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.66 (t, J=7.4 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 5.33-5.29 (m, 1H), 4.77 (d, J=6.2 Hz, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 2.60 (s, 3H). MS=479 (MH)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1.[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:8]([NH:7][C:5]1[S:6][C:2]([C:26]2[CH:27]=[CH:28][C:22]3[O:21][CH2:20][CH2:19][N:18]([C:16]([O:15][C:12]([CH3:13])([CH3:11])[CH3:14])=[O:17])[CH2:24][C:23]=3[CH:25]=2)=[CH:3][N:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)s1
Temperature: 95 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
A mixture of N-(5-bromo-1,3-thiazol-2-yl)acetamide (1.00 g, 4.5 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (1.59 g, 5.4 mmol), potassium carbonate (2.50 g, 18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.33 g, 0.45 mmol), 1,4-dioxane (20 mL), and water (2 mL) was degassed with nitrogen for 2 min, and then stirred at 95° C. for 16 h. The reaction mixture was cooled, diluted with ethyl acetate (100 mL), and filtered through celite. The filtrate was washed with brine (2×30 mL), dried over sodium sulfate, and concentrated. Column chromatography on silica (gradient 20-85% ethyl acetate in hexane) gave 1,1-dimethylethyl 7-[2-(acetylamino)-1,3-thiazol-5-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.99 g, 56% yield). MS (EI) for C19H23N3O4: 390 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]1[CH2:21][C@@H:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][N:18]1[C:30](OC(C)(C)C)=[O:31])[CH2:9][CH2:10]C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C[C@@H]1C[C@@H](OCC2C=CC=CC=2)CN1C(OC(C)(C)C)=O)CCC(OCC)=O)C1C=CC=CC=1.Cl.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:30](=[O:31])[N:18]2[CH2:19][C@H:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][C@@H:17]2[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)C[C@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)CCN(Cc1ccccc1)C[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1CCN(Cc2ccccc2)C[C@H]2C[C@@H](OCc3ccccc3)CN12
Temperature: 22.5 °C
Reaction time: 22 h
Yield: 35 %

Procedure:
To a 2:3 mixture of tert-butyl (2R,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate and tert-butyl (2S,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate (25 g, 0.050 mol, Part B) in methanol (125 mL) was added a solution of 4.0 M HCl/dioxane (125 mL) while maintaining the internal temperature below 5° C. The reaction mixture was allowed to stir at 20-25° C. for 22 hours and was then concentrated. The residue was stirred with toluene (250 mL) and 1 M sodium carbonate solution (250 mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The toluene filtrate was heated to reflux at 115° C. for four hours and was then concentrated. The isomers were separated by silica gel column chromatography eluted with ethyl acetate/hexane (60:40) to give (8R,9aR)-2-benzyl-8-(benzyloxy)octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (6.2 g, 35%) as dark brown oil. HPLC (column: Agilent ZORBAX® RX-C8, 150 mm×4.6 mm, 5 μm; gradient: 10-80% acetonitrile in 0.1% phosphoric acid/water over 13 minutes with a hold at 80% for an additional five minutes; flow rate: 1.0 mL/minute; temperature: 30° C.). Retention time for the titled isomer was 7.147 minutes and for the (8R,9aS) isomer, 6.704 minutes. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.23 (m, 10 H), 4.62-4.47 (m, 2 H), 4.11-3.96 (m, 2 H), 3.83-3.75 (m, 1 H), 3.64-3.56 (m, 3 H), 3.02-2.74 (m, 3 H), 2.61-2.53 (m, 1 H), 2.47-2.36 (m, 3 H), 1.88-1.79 (m, 1 H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:18]1[C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[NH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 20 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
N-Bromosuccinimide (6.84 g, 38.42 mmol) was added portionwise to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.56 mmol) in DCM, dry (125 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 20° C. for 1 hour. The reaction mixture was evaporated and the resulting brown solid was triturated with water to give a purple solid which was collected by filtration. The crude solid was triturated with hot MeOH to give a solid which was collected by filtration. The hot trituration was repeated to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.23 g, 69.1%) as a cream solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](=[N:21][NH:22][C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)=[O:24])[CH3:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:19](=[N:21][NH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[O:24])[CH3:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=1
Reactant: CCCCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-1-methyl-5-(4-n-pentylphenyl)-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.121 mmol, 66.5 mg), methanol (3.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.605 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.605 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (40.4 mg, yield 74%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH2:14][NH2:15])[CH2:6]1)=O.CC(C)([O-])C.[Na+]>CO>[O:2]=[C:3]1[NH:15][CH2:14][CH:7]2[CH2:6][CH:5]1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: COC(=O)C1CC(CN)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCC2CC1c1ccccc12
Temperature: 25 °C

Procedure:
To a solution of 3-aminomethyl-indan-1-carboxylic acid methyl ester (assume 20.0 mmol, 1 equivalent) in 50 mL of methanol (this was the crude reaction mixture from the prior step, Example 60C) was added 3.84 g of sodium tert-butoxide (40.0 mmol, 2.0 equivalent). The reaction mixture was heated to a reflux for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between 60 mL of ethyl acetate and 40 mL of 5% aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice more with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide a solid material. Recrystallization of the solid from 10 mL of toluene provided white crystals of the title compound (1.78 g, 51%). mp=172–173° C.;. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 5.62 (s, 1H), 3.68 (dd, J=11.2, 4.1 Hz, 1H), 3.55 (d, J=3.7 Hz, 1H), 3.43–3.37 (m, 1H), 3.18 (d, J=11.2 Hz, 1H), 2.52–2.45 (m, 1H), 2.32 (d, J=11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 173.6, 144.7, 144.6, 128.0, 127.7, 123.2, 122.9, 49.3, 47.9, 39.1, 38.4; IR (neat, cm−1): 3218, 2949, 2872, 1666, 1485, 1459, 1400, 1328, 1303, 1288, 1250, 1215, 1122, 1104, 1045, 1004, 946, 910, 756, 730, 643, 613; Anal. Calcd for C11H121NO: C, 76.28; H, 6.40; N, 8.09; Found: C, 75.94; H, 6.27; N, 7.99.
Reaction SMILES: [OH-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].O1CCCC1.Br.[CH2:16]1[CH2:20][O:19][C:18]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][NH2:30])[C:27]=3[C:17]1=2>O>[CH2:16]1[CH2:20][O:19][C:18]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][NH:30][C:3](=[O:5])[CH3:4])[C:27]=3[C:17]1=2
Reactant: NCCC1CCc2ccc3c(c21)CCO3
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Aqueous 1 N sodium hydroxide solution (1.5 ml) and acetic anhydride (0.050 ml, 0.528 mmols) were added to a tetrahydrofuran (1.5 ml) solution of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrobromide (0.10 g, 0.352 mmols), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether/hexane to obtain 0.057g (yield: 66%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18].C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:22]([OH:23])=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH3:7])[N:6]=2)[C:17]=1[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1F
Reactant: Cc1nc(N)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nc2nc(O)c(-c3ccc(F)cc3F)c(O)n2n1

Procedure:
4 g (40.95 mmol) 3-Amino-5-methyl-1,2,4-triazole, 10 g diethyl (2,4-difluorophenyl)malonate and 9 g tributylamine are stirred at 180° C. over night. The solution is diluted with 2N NaOH solution and water and the resulting mixture is extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified at 0° C. with concentrated HCl. The precipitate is collected by filtration, washed with water and dried. This product (4.47 g=33.4%) is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[C:9]2[C:31]([O:33]CC)=[O:32])=[CH:5][CH:4]=1.[Li+].[OH-].Cl>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[C:9]2[C:31]([OH:33])=[O:32])=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1c(OCCOc2cccc3ccccc23)c2ccccc2n1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(C(=O)O)c(OCCOc3cccc4ccccc34)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 101C (80 mg) in tetrahydrofuran (2 ml), methanol (1 ml) and water (1 ml) was added LiOH (100 mg). The mixture was stirred at room temperature overnight. The mixture was then acidified with 5% HCl and extracted with ethyl acetate (200 ml). The organic layer was washed with water, brine and dried over Na2SO4. After concentration of the solvent, the residue was dissolved in DMSO/methanol (1:1, 1.5 ml) and purified via reverse phaseHPLC. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.99 (m, 1H), 8.01 (m, 1H), 7.86 (m, 1H), 7.73 (m, 1H), 7.46 (m, 6H), 7.27 (m, 1H), 6.98 (m, 3H), 6.74 (m, 2H), 5.70 (s, 2H), 4.64 (m, 2H), 4.48 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:18][C:19](=O)[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:22]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:21]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:19](=[O:18])[C:20]2[CH:21]=[C:22]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: NCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCc1ccccc1)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a flamed dried round bottom flask with 3-phenyl-1-propylamine (0.404 mL, 2.84 mmol) and THF (5 mL) cooled to −78° C. was added n-BuLi (1.14 mL, 2.5 M in hexane, 2.84 mmol) dropwise over a 5 min. period. The resulting solution was stirred at this temperature for 0.5 h, warmed to 0° C. for 10 min., and then cooled back to −40° C. This lithiated amine solution was added dropwise to a solution (at −40° C.) of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.350 g, 0.811 mmol) in THF (15 mL) over 5 min. The final mixture was stirred at −40° C. for 15 min. and then warmed to room temperature for 15 min. At this point, the reaction mixture was quenched with H2O (20 mL) and diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/hexane gradient) to afford the product (0.347 g, 82%) as a solid; 1H NMR (CDCl3) δ1.44-1.68 (bs, 1H), 2.01 (t, J=7.0 Hz, 2H), 2.74 (t, J=7.7 Hz, 2H), 3.27-3.46 (m, 4H), 3.53 (dd, J=7.7, 14.7 Hz, 2H), 5.94-6.08 (bs, 1H), 7.02-7.13 (m, 1H), 7.13-7.33 (m, 4H), 7.33-7.46 (m, 4H), 7.46-7.54 (m, 2H), 7.61 (s, 4H); mass spectrum [(+) APCI], m/z 520/522 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.CS(Cl)(=O)=O.C(N(CC)CC)C.S([O-])(=O)(=O)C.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.ClCCl>[N:26]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: OCC1CCOCC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL round bottom flask is placed (tetrahydro-2H-pyran-4-yl)methanol (350 mg, 3 mmol), followed by dichloromethane (DCM, 15 mL). The solution is cooled to 0° C. and is then treated with methanesulfonyl chloride (0.24 mL, 3.15 mmol) and triethylamine (0.88 mL, 6.3 mmol). The reaction is complete after 30 min. and is then quenched with water and diluted with DCM (10 mL). The layers are then partitioned, and the aqueous layer is extracted with DCM (3×10 mL). The combined organics are dried over Na2SO4, filtered and concentrated. The crude mesylate is then dissolved in DMF (10 mL), to which sodium azide (410 mg, 6.3 mmol) is added and then heated to 75° C. for 4 h. The reaction is then cooled to room temperature, quenched with water (10 mL) and extracted with diethyl ether (3×20 mL). The combined organics are then washed with water (3×10 mL), dried over MgSO4, filtered, and concentrated to give 4-(azidomethyl)-tetrahydro-2H-pyran as a colorless liquid. 1H NMR (CDCl3, 400 MHz) δ 4.01-3.97 (m, 2H), 3.39 (td, J=11.9, 2.1 Hz, 2H), 3.18 (d, J=6.8 Hz, 2H), 1.86-1.75 (m, 1H), 1.67-1.64 (m, 2H), 1.40-1.29 (m, 2H).
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[NH2:1][C:24]1[CH2:25][CH2:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=1
Reactant: c1ccc2ncccc2c1
Reactant: [NH2-]
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC1=Nc2ccccc2CC1
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 46.8 g (1.2 moles) of sodamide. 400 cc of toluene containing 0.5 cc of oleic acid and 129.2 g (1.0 mole) of quinoline was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring for 2 hours within a range of 138°-148° C. No hydrogen evolution was observed. The autoclave was cooled and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed (external cooling) with 150 cc of water. The maximum temperature was 30° C. The hydrolyzed mixture contained organic crystalline material. In order to dissolve the crystals, 200 cc of 4-picoline was added and the mixture thoroughly stirred. The aqueous phase was allowed to settle and was removed. The organic phase was placed under vacuum at 40° C. to remove most of the residual ammonia. It was then treated with dry ice and filtered to remove carbonates. The filtrate was topped to a liquid temperature of 110° C. at 50 mm Hg. To the residue was added about 2 parts of toluene and the solution was allowed to crystallize. The mixture was filtered to give 57.4 g of 2-amino-3,4-dihydroquinoline, m.p. of 134.9°-136.3° C. The dihydroquinoline was hydrolyzed in boiling water to give 3,4-dihydrocarbostyril m.p. 165.7°-167.1° C. It is reported in Tetsuji et al., J. Heterocycle Chem., 2, 330 (1965) that the Chichibabin amination of quinoline in toluene at atmospheric pressure gave only 2-aminoquinoline. Derivatives of 3,4-dihydrocarbostryril have anti-inflammatory and blood platelet coagulation activities as claimed by Nakagawa et al., Japan. Kokai 77 73,866.