Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]1([NH:13]C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[NH:13]1[C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2](=[O:3])[C:1]1=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2C1=O

Procedure:
A solution of oxalyl chloride (175 mL, 254.6 g, 2.01M) was cooled to 5°, and a solution of diphenylamine (320 g, 1.89M) in toluene (580 mL) added over 8 minutes. The mixture was heated to 50°-65° for 74 minutes. The mixture was then heated to 125° to distill toluene and excess oxalyl chloride; total distillate collected was 630 mL. The solution was then refluxed at 125°±2° for 20 hours to form indoline-2,3-dione. The mixture was cooled to 104°, and a solution of 4-picoline (215 mL, 205.7 g, 2.21M) in acetic acid (750 mL) was added over 17 minutes. The mixture was heated to 130° to remove excess toluene via acetic acid/toluene azeotrope. Additional acetic acid (750 mL) was added during the distillation. A total of 875 mL distillate containing 260 mL toluene was collected. The mixture was cooled to 115°, and acetic anhydride (360 mL, 389.5 g, 3.81M) added over 10 minutes while heating to 120°-130°. The mixture was stirred at 120°±2° for 1.75 hours, and then cooled to 76°. Water (530 mL) was added over 7 minutes followed by isopropanol (430 mL) while maintaining the temperature between 82° and 63°. The mixture was cooled to ambient temperature overnight, then to 0°-5°. The crude product was collected by filtration, washed with isopropanol (2.16 l) and water 1.64 l). Drying in a vacuum oven at 80°-90° yielded the title compound (422.6 g, 75%) as an orange crystalline solid. M.P.: 160.1°-161.9°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:7][CH3:8])[O:5][CH:6]=1.C(=O)([O-])[O-:10].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([S:7]([CH3:8])=[O:10])[O:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc(C)co1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1coc(S(C)=O)n1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
4-Methyl-2-methylthiooxazole (6.06 g, 0.047 m) in dry chloroform (50 ml) was cooled to 0° C. with vigorous stirring and anhydrous sodium carbonate (6.06 g, 0.057 m) added. 96% 3-Chloroperbenzoic acid (8.90 g, 0.0495 m) in dry chloroform (100 ml) was then added dropwise over 45 minutes and the mixture stirred for a further 45 minutes at 0° C. Solid sodium sulphite (2.0 g) was added and the mixture allowed to warm to room temperature. The mixture was then filtered, the filtrate evaporated and the resulting oil was distilled under vacuum to give the title compound as a colourless oil 6.48 g (95%), b.p. (airbath)76° C./0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (N I+): m/z=423.1, tR (minutes, Method D)=0.81
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:22])[CH:19]([CH3:21])[CH3:20]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)CO
Product: CC(C)COC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and isobutanol there is obtained isobutyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 1.07 [d, CH(CH3)2 ], 2.1 (m, 1H), 3.95 (d, CH2), 4.25 (s, 4H), 4.55 (broad s, NH), 7.3-7.7 (8H);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3c(F)cccc3F)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained in an inert atmosphere of nitrogen, was placed a solution of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in 1,4-dioxane/water (60/15 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.87 mmol, 1.3 equiv), sodium carbonate (180 mg, 1.68 mmol, 2.5 equiv), and tetrakis(triphenylphosphane)palladium (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath and then concentrated under vacuum. The resulting solution was diluted with 50 mL of dichloromethane, washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 280 mg (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (1 mL) followed by the addition of 1-ethylpiperazine (121 mg, 1.63 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. NaBH(OAc)3 (173 mg, 0.81 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (135 mg, yield 47%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (t, 3H), 2.36-2.44 (m, 1H), 2.74-3.11 (m, 8H), 4.01-4.10 (m, 3H), 4.33 (dd, 1H), 4.78 (dd, 1H), 7.13-7.31 (m, 10H), 7.37 (d, 1H), 7.47 (s, 1H), 7.58 (t, 3H); LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12].[H][H]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1C
Reaction time: 0.17 h

Procedure:
To the solution of 1-methoxy-2-methyl-4-nitrobenzene (10 g, 60 mmol) in EtOH and EtOAc (250 mL, 3:2) was added 10% Pd/C (2 g). The mixture was stirred for 24 h under one atmosphere of hydrogen. Celite was added and the mixture was stirred for 10 min. The mixture was filtered through a pad of Celite. Concentration under reduced pressure gave 4-methoxy-3-methylaniline. LCMS-ESI+ (m/z): 138.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1)#[N:2].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][N:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
6-Cyano-nicotinic acid (120 mg, 810 μmol) was suspended in toluene (1 mL) and thionyl chloride (119 μL, 1.62 mmol) was added dropwise followed by one drop of DMF. The reaction mixture was refluxed for 2.5 hours and then allowed to cool to room temperature for 18 hours. The solvents were removed in vacuo and the residue was azeotroped with toluene to furnish the title compound as a brown oil (134 mg) which was used in further experiments without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:21])([CH3:20])[CH:10]=[C:9]3[CH3:22])[C:6](=[O:23])[O:5]2.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:33][CH2:34]C)(=O)C.C(OCC)C>CN(C)C=O>[CH3:30][O:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:20])([CH3:21])[CH:10]=[C:9]3[CH3:22])[C:6](=[O:23])[O:5]2
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cc(O)ccc13
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1ccc2c(c1)oc(=O)c1c3c(ccc12)NC(C)(C)C=C3C
Temperature: 50 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 8-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-1-(4), 1.00 g, 3.25 mmol), chlorodimethylether (420 μL, 5.53 mmol) and potassium carbonate (1.35 g, 9.77 mmol) was suspended in anhydrous N,N-dimethylformamide (15 mL) and stirred at 50° C. overnight. After cooling down, ethyl acetate (100 mL) and diethylether (100 mL) were added thereto. The whole was washed with water (150 mL, 100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (747 mg) as a yellow solid. (Yield 66%)
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(#N)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCCCCBr
Reactant: Nc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCNc1ccc2ccc3cccc4ccc1c2c34

Procedure:
A mixture of 1-aminopyrene (5 g), potassium carbonate (15 g) and ethyl 6-bromohexanoate (10 g) in 60 mL acetonitrile was refluxed for 24 hours. The solvent was removed and the product was purified by a silica gel column eluting with EtOAc/hexane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20]C=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:16](=[C:12]1[NH:11][C:10](=[O:24])[C:9](=[CH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)[NH:14][C:13]1=[O:15])[C:17]1[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccncc1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=Cc2ccc(OCc3ccncc3)cn2)c(=O)[nH]c1=Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
A mixture of Compound C (1 g), 4-(bromomethyl)pyridine (2 g), sodium carbonate (2 g), and DMF (50 mL) were stirred at 100° C. for 16 hr and cooled at an ice bath to produce a yellow precipitate. The precipitate was then collected and washed with water to give 0.38 g (30%) of 3-benzylidene-6-((5-(pyridin-4-ylmethoxy)pyridin-2-yl)methylene)piperazine-2,5-dione (Compound 1). mp 254-255° C.; 1H-NMR (400 MHz, CDCl3), 5.26 (s, 2H) 6.78 (s, 1H), 7.11 (s, 1H), 7.31-7.59 (m, 9H), 8.20 (s, 1H), 8.48 (dd, J=2.8 Hz, 1H),), 8.72, (s, 2H), 12.50 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4](C)[C:5]([C:7]1[N:8]=[C:9]([CH3:19])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:6].C(N(CC)CC)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>C1COCC1>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([CH3:19])[S:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[O:6]
Reactant: Cc1nc(C(=O)N(C)CCN)c(-c2ccc(F)cc2)s1
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)NCCNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (2-amino-ethyl)-methyl-amide, D5 (120 mg, 0.41 mmol) in THF (7 ml) was treated with triethylamine (0.057 ml) and 2-chlorobenzoxazole (0.047 ml, 0.41 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h then the volatiles removed in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate-pentane) to afford the title compound as a white solid (97 mg, 58%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:16]1[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][OH:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][O:40][C:34]1[CH:35]=[CH:16][C:17]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]2)=[CH:32][CH:33]=1
Reactant: OCCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCCC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
Diisopropyl azodicarboxylate (0.97 mL) was added to a solution of tert-butyl 4-(hydroxyphenoxy)piperidine-1-carboxylate (1.2 g), 3,3,3-trifluoro-1-propanol (0.56 g) and triphenylphosphine (1.5 g) in dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated at reduced pressure. This resulting mixture was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give tert-butyl 4-[4-(3,3,3-trifluoropropoxy)phenoxy]piperidine-1-carboxylate as a white solid (0.6 g); NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.66-1.77 (m, 2H), 1.83-1.94 (m, 2H), 2.52-2.66 (m, 2H), 3.24-3.34 (m, 2H), 3.65-3.75 (m, 2H), 4.11 (t, 2H), 4.27-4.37 (m, 1H), 6.78-6.89 (m, 4H); Mass Spectrum: M+H+ 390 and (M-tBuOCO)+H+ 290.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:23]1C2C(=CC=C(C(C3C=CC=CC=3OC)CC(NC)=O)C=2)C=[CH:24]1>>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([CH:5]([C:6]3[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=3)[CH2:4][C:3]([NH:23][CH3:24])=[O:2])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: COC(=O)CC(c1ccc(Cl)cc1)c1ccc2cc[nH]c2c1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-(4-chloro-phenyl)-N-methyl-propionamide XLIV (370 mg, 97%) was prepared from 3-(1H-indol-6-yl)-3-(4-chloro-phenyl)-propionic acid methyl ester following the procedure for 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide XXXVIII (see Example 9).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([O:14]C)=[O:13])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CC(O)=O>CO>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=[O:13])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)nc(C(=O)OC)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(C)nc(C(=O)O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 68 4 mg (0.155 manol) 6-butyl-4-methoxycarbonyl-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine in 5 mL methanol was added ~0.300 mL 10% NaOH. After stirring at room temperature for 2.5 hours, the mixture was acidified with ~0.500 mL HOAc. Volatiles were removed in vacuo. The crude material was redissolved in methanol along with a couple of drops of TFA, then was HPLC'd using the following conditions: Rainin Dynamax® C-18 column, 25×2.14 cm w/Guard Column; gradient of acetonitrile in water 5 to 100% over 40 minutes at 5 mL/minute; gradient held at 82% for 7 minutes. A yield of 66.1 mg (100%) of the title compound was obtained. Rf 0.14 in 1/30/69 NH4OH/MeOH/CH2Cl2, visualized by UV; 1H-NMR (300 MHZ, CDCl3): δ~9.7-8.8 (v br s 2H) 7.97 (m, 1H), 7.52 (m, 2H), 7.37 (m, 1H), 7.00 (br s, 4H), 4.51 (br s, 2H), 2.86 (3 line m, 2H), 2.75 (br s, 3H), 1.62 (m, 2H), 1.36 (m, 2H), 0.88 (3 line m, 3H); MS(FAB) m/e 429 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:19]=1.[N+]([O-])(O)=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:21])[C:11]3[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:19]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1ccc2c(c1)C=Cc1ccc(C=O)cc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc2c(c1)C=Cc1ccc(C=O)cc1S2=O
Reaction time: 0.5 h

Procedure:
Dissolve 8-methylthiodibenzo[b,f]thiepin-3-carboxaldehyde (5 mmole) in methylene chloride (100 ml); and while cooling the solution in an ice-bath, add a 1M solution of 90% nitric acid in methylene chloride (5 ml). Monitor the reaction mixture by tlc after 30 minutes, and add the nitric acid solution in small increments until starting material has disappeared. Treat the reaction mixture with sodium bicarbonate solution to remove acidic substances. Dry the organic solution, evaporate to dryness, and purify the title product by column chromatography on silica gel using 1:4 ethyl acetate/toluene for elution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][NH:24][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:25]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(c(N3CCOCC3)c1)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(cccc2N2CCOCC2)C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C(C)=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:10]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: O=C(Nc1cccnc1)c1c(O)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 53.2 %

Procedure:
A mixture of 2.43 g (10.2 mmols) of ethyl 4,5-dihydro-7-hydroxy-5-oxothieno[3,2-b]pyridine-6-carboxylate [J. Chem. Res. (S), 6 (1980); J. Chem. Res. (M), 113 (1980)], 1.00 g (10.6 mmols) of 3-aminopyridine, 50 ml of xylene and 10 ml of dimethylformamide was heated at 140° C. for an hour. After completion of the reaction, insoluble matters were filtered and recrystallized from dimethylformamide to give 1.56 g (yield: 54%) of Compound 1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]([OH:17])=O)(O)=[O:2].[NH4+:18].[OH-]>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][C:8]=1[O:10][CH3:11])[C:1](=[O:2])[NH:18][C:15](=[O:17])[CH2:14]2
Reactant: COc1cc(CC(=O)O)c(C(=O)O)cc1OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(cc1OC)C(=O)NC(=O)C2

Procedure:
A solution of 8.2 g (34.1 mmol) of 2-carboxy-4,5-dimethoxybenzeneacetic acid (Tetrahedron 1975, 31, 2607) in 17 ml of conc NH4OH is evaporated to dryness. This operation is repeated. The resulting tan solid ammonium salt is suspended in 34 ml of 1,2-dichlorobenzene. The stirred mixture is boiled in an oil bath at 210° while collecting some distillate during 90 m. The cooled mixture is stirred in hexane and H2O, and the resulting solid is collected by filtration. The white solid is stirred in satd NaHCO3 for 15 m, filtered, washed with H2O, and dried to give 3.45 g (46%), mp 234-238°; MS (ES−) m/z 220.1 (M−H)−1.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])C=O)[CH3:9].NC1C=CC=CC=1.S(=O)(=O)(O)O>N1C=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:3]=[CH:2][C:1]([OH:7])=[O:6])[CH3:9]
Reactant: O=C(O)CC(=O)O
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: Nc1ccccc1
Product: CCOc1cc(C=CC(=O)O)ccc1O
Reaction time: 3 h
Yield: 52.9 %

Procedure:
Malonic acid (1.56 g) and pyridine (3.0 ml) were placed in an egg-plant type flask (100 ml). Further, 3-ethoxy-4-hydroxybenzaldehyde (1.66 g) and aniline (30 μl) were added thereto and a reaction was performed at 55° C. for 3 hours. The reaction solution was acidified by adding dilute sulfuric acid. The crude crystals were obtained by filtration, washed with water, and then dried to obtain the above-identified compound (1.1 g, 56.1%) as a light yellowish crystal. Melting point: 157°-158° C.