Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Yield: 95.2 %

Procedure:
This compound was prepared according to a process similar to that described in stage 6.3, by reacting 5 g (16.26 mmol) of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, prepared according to the protocol described in stage 6.1, with 3.46 g (21.13 mmol) of 3-acetylphenylboronic acid, in the presence of a 2M aqueous solution of sodium carbonate (90 ml) and of 0.94 g (0.81 mmol) of tetrakis(triphenylphosphine)palladium in 180 ml of a mixture of acetonitrile and toluene (v/v). 5.37 g of expected product are obtained
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([OH:17])(=[O:16])[CH:15]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: CC(=O)O
Product: O=C(O)C=Cc1ccccc1
Yield: 76.3 %

Procedure:
A mixture of 129 g of 1,1,1,3-tetrachloro-3-phenylpropane, 74 g of glacial acetic acid and 39 g of Wolfatit OK 80 cation exchanger is heated to 118° to 124° C. for 15 h. The cation exchanger is removed from the hot reaction mixture by filtration. After cooling the mixture, filtration of the crystals and their washing with water, 56.5 g of cinnamic acid is obtained. Condensation of the filtrate followed by filtration of the crystals gives another 9.5 g of cinnamic acid with total yield of 89% (melting point after recrystallization 128° to 135° C., min. 98% purity).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH2:6][CH2:5][C:4](=[O:7])[C:3]=2[CH3:8])=[CH:13][CH:12]=1
Reactant: CC1=C(Br)CCC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(C2=C(C)C(=O)CC2)cn1
Yield: 92 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 6-methoxypyridine-3-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography yielded the product (138 mg, 92%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.41 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8.5, 2.5 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.99 (s, 3H), 2.92-2.87 (m, 2H), 2.56-2.53 (m, 2H), 1.99 (t, J=1.9 Hz, 3H). 13C (75 MHz, CDCl3): δ 208.9, 164.4, 162.6, 146.4, 137.4, 135.9, 125.4, 110.9, 53.8, 33.8, 28.7, 10.2. LCMS (ESI): mass calcd for (C12H13NO2) m/z 203.09; measured [M+H]+: m/z 204.09.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:30]([OH:33])[CH2:31][OH:32])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.O1CCOCC1>CO>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:9]1[C:8]2[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[C:6]([CH:30]([OH:33])[CH2:31][OH:32])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(C(O)CO)cc23)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cc(C(O)CO)cc2c(NCc3cccc(N)c3)ncnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [3-({[8-(aminocarbonyl)-6-(1,2-dihydroxyethyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate (25.00 mg; 0.06 mmol; 1.00 eq.) in methanol was added 4.0M hydrogen chloride in dioxane (0.14 ml; 4.00 M; 0.55 mmol; 10.00 eq.). The reaction mixture was stirred at RT for 1 h and evaporated off the solvent to obtain the title compound MS (M+1) 354
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][N:7]([CH2:31][C:32]([O:34]C)=[O:33])[C:8](=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1>>[C:5]([CH2:6][N:7]([C:8](=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)[CH2:31][C:32]([OH:34])=[O:33])([OH:36])=[O:4]
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-methoxy-2-oxoethyl)-N-[3-(tetradecyloxy)benzoyl]glycine methyl ester as in Example 4 gave N-(carboxymethyl)-N-[3-(tetradecyloxy)benzoyl]glycine, mp 96°-99°.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]([CH3:34])[C:31](=[O:35])[N:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:29]2=[O:52].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:30]2[C:29](=[O:52])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[N:32]([CH3:34])[C:31]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Temperature: 90 °C
Yield: 71.8 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (100 mg, 0.262 mmol), 8-fluoro-1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (161 mg, 0.393 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) and 2 M aqueous K3PO4 (0.26 mL, 0.524 mmol) in THF (2 mL) in a pressure reaction vial was heated at 90° C. for 2.5 h. The cooled mixture was concentrated, and the residue was purified by column chromatography on silica gel (40 g), eluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3). The resulting impure product was again purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give 3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl) -7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (110 mg, 68% yield). Mass spectrum m/z 567 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.17-8.10 (m, 1H), 7.76 (s, 1H), 7.69 (d, J=1.1 Hz, 1H), 7.59-7.53 (m, 1H), 7.48 (ddt, J=13.9, 8.1, 1.8 Hz, 1H), 7.39 (dd, J=12.4, 7.8 Hz, 2H), 7.28-7.19 (m, 2H), 6.97 (t, J=8.5 Hz, 1H), 3.87-3.93 (m, 3H), 1.87 (d, J=1.8 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.C([N:12](CC)CC)C.[CH:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]1[CH2:29][CH:28]([CH2:30]O)[CH2:27][CH2:26][N:21]12>ClCCl>[NH2:12][CH2:30][CH:28]1[CH2:27][CH2:26][N:21]2[C:22]3[C:18]([CH:19]=[C:20]2[CH2:29]1)=[CH:17][CH:25]=[CH:24][CH:23]=3
Reactant: CCN(CC)CC
Reactant: OCC1CCn2c(cc3ccccc32)C1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: NCC1CCn2c(cc3ccccc32)C1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2.4 g of methanesulfonic anhydride and 2 ml of triethylamine were added to a stirred solution of 2.01 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol in 40 ml of dichloromethane under a nitrogen atmosphere. After 18 hours, the mixture was washed with saturated sodium bicarbonate solution, dried and evaporated to an oil. Then, 1.8 g of this oil were dissolved in 10 ml of isopropanol and 5 ml of 33% aqueous ammonia and the mixture was heated to 80° C. for 10 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was dried and evaporated to give 1.3 g of 8-aminomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole of melting point 85°-90° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1

Procedure:
A mixture of 2-chlorobenzenesulfonic acid 3-benzyloxy-5-methylphenyl ester (4.66 g, 12 mmol), as prepared in the preceding step, and 10% palladium on carbon (500 mg) in tetrahydrofuran (80 mL) was hydrogenated (balloon) for 3 h. The catalyst was removed by filtration through diatomaceous earth (tetrahydrofuran washes) and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (methylene chloride) to give the title compound as a pale-yellow solid (3.20 g, 89%, 1 H-NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 5.24 (s, 1H), 6.44 (t, 1H), 6.53 (d, 2H), 7.38 (dt, 1H), 7.60 (m, 2H), 7.96 (dd, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[C:21]([N:31]1[CH2:49][CH2:48][CH2:47][C@H:32]1[C:33]([NH:35][C:36]([C:44](O)=[O:45])=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:44](=[O:45])[C:36](=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:35][C:33](=[O:34])[C@@H:32]1[CH2:47][CH2:48][CH2:49][N:31]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of 0.759 g (0.0036 mole) of L-phenylalanine methyl ester hydrochloride and 40 ml of ethyl acetate was cooled in an ice-bath and 15 ml of cold 50% potassium carbonate solution was added. The mixture was equilibrated, and the ethyl acetate layer was separated and dried over anhydrous Na2SO4 at 0°. To the solution 1.129 g (0.003 mole) of the azlactone of N-carbobenzoxy-L-prolyl-dehydrophenylalanine was added. The reaction mixture was then refluxed for 8 hours, cooled and washed with N-hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residual crystals were recrystallized from ethyl acetate/petroleum ether giving 1.473 g (88%) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine methyl ester, mp 161°-163.5°, RfA 0.95, [α]D26 =-94.3° (c, 1% in EtOH); ir (CHCl3) 1735 (C=O) 1690-1670 (C=O), 1630 cm-1 (C=C); NMR (CDCl3) δ1.5-2.4 (m, 4H, Pro ring), 3.0-3.33 (m, 2H, --CHCH2Ph), 3.33-3.57 (m, 2H, Pro ring) 3.63 (s, 3H, --COOCH3), 4.17-4.53 (m, 1H, --CH--CH2Ph), 4.67-5.0 (m, 1H, Pro ring), 5.02 (br.s., 2H>NOCOCH2Ph) 6.83-7.47 (m, 11H, ArH and PhCH=C<), 7.9-8.1 ppm (b, 2H, NH, exchang by D2O).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[C:13](C(O)=O)=[N:12]2)[CH:7]=[CH:8][C:9]=1[CH3:10])([OH:3])=[O:2].[OH-].[Na+].SCC(O)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[O:17]=[C:16]1[NH:15][C:14](=[O:18])[CH:13]=[N:12][N:11]1[C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([CH:5]=1)[C:1]([OH:3])=[O:2]
Reactant: Cc1ccc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc1C(=O)O
Agent: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Temperature: 102.5 °C
Yield: 73.9 %

Procedure:
2-(3-Carboxy-4-methyl-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (110 gm) was added to 8 volumes of water with 2.4 equivalents of sodium hydroxide and 1.1 equivalents of mercaptoacetic acid. The reaction mixture was heated to reflux (100-105° C.) for approximately 18 hours at which point the reaction was complete by HPLC. 30% Sodium hydroxide and toluene were added and the resulting mixture was stirred. Upon settling a large interface was noted. More water, toluene and some ethyl acetate were added. The interface was minimized. The water layer was separated and treated with 2N HCl. At pH 2 solids precipitated out and the slurry was cooled to <10° C. The solids were filtered off in a slow filtration and dried in a vacuum oven to give 69 gm of the title compound.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N+:23]1([O-])[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[Na+]>CO.O>[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[CH3:21][N:14]([CH2:13][CH2:12][CH2:11][O:10][N+:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)c2ccccc2)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Cc1cccc[n+]1OCCCN(C)c1ccccc1

Procedure:
3-(N-Methylanilino)propyl p-toluenesulfonate (21.2 g, 0.0665 mole) and 2-picoline-N-oxide (7.3 g, 0.0665 mole) were heated together on a steam bath for 1/2 hour. The mixture was allowed to cool, then dissolved in methanol (50 ml). A solution of sodium perchlorate (9.3 g, 0.076 mole) in water (12 ml) was added and the mixture chilled. The solid which separated was collected and washed with a little 90% methanol, then with ether. The yield was 14.3 g (60%), m.p. 111°-113° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9].O.[NH2:20][NH2:21]>C(O)C>[CH2:6]([CH:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:21][NH:20][C:3](=[O:2])[CH2:4]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(CC(=O)OC)C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCC1CC(=O)NN=C1c1ccccc1

Procedure:
A solution of 3-benzoyl-heptanoic acid methyl ester (4.72 g, 19 mmol) and hydrazine monohydrate (4.6 ml, 95 mmol) in ethanol (50 mL) is reflux for 12 hours. The solvent and excess hydrazine monohydrate is removed in vacuo and the residue is partitioned with EtOAc (80 mL) and water (80 mL). The layers are separated and the organic phase is washed with brine (60 mL), dried (Na2SO4) and evaporated in vacuo. Hash column chromatography of the residue (silica gel, 2:1 hexane, EtOAc) provides a creamy solid. LC-MS (M+1) 231. 1H NMR (δ, CDCl3) 8.84 (s, 1H), 7.72-7.79 (m, 2H), 7.37-7.43 (m, 3H), 3.19-3.30 (m, 1H), 2.62 (d, J=6.8 Hz, 2H), 1.52-1.62 (m, 2H), 1.21-1.43 (m, 4H), 0.87 (t, J=7.8 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>N1C=CC=CC=1>[C:1]1([CH2:14][O:15][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Fluorenylmethanol (0.90 g, 4.5 mmol) and dimethylaminopyridine (50 mg) were dissolved in 10 ml dry pyridine. Succinic anhydride (0.50 g, 5.0 mmol) was added and the solution stirred overnight. The solvent was removed under reduced pressure, sodium bicarbonate added (50 ml), the solution extracted with ethyl acetate (50 ml), and the organic layer discarded. The aqueous layer was acidified to pH 2, extracted with ethyl acetate (2×100 ml), washed with brine, and the solvent removed under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexane 2:1 as eluant) to give 0.86 g product (2.9 mmol, 64%). 1H NMR: (CDCl3, 200 MHz) δ7.8-7.26 (8H, m, ArH), 4.43 (2H, d, J=6.5 Hz, CHCH2OCO), 4.23 (1H, t, J=6.5 Hz, CHCH2OCO), 2.70 (4H, s, OCOCH2CH2COO).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:23]2[CH:24]=[CH:25][C:26]([F:27])=[C:21]([Cl:20])[CH:22]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1nc(C(C)(C)NC(=O)c2cccc(Br)n2)no1
Product: Cc1nc(C(C)(C)NC(=O)c2cccc(-c3ccc(F)c(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 267 b, 6-bromo-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 267a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials, LC-MS (UV peak area/ESI) 91%, 375.1018 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C[O-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20]>>[CH3:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH:8]([C:18]([O:19][CH3:20])=[O:21])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: Cc1cc2c(cc1C)C(=O)CCCO2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCOc2cc(C)c(C)cc2C1=O

Procedure:
A mixture of 7,8-dimethyl-3,4-dihydro-1-benzoxepin5(2H)-one (1.3 g), sodium methoxide (2.0 g) and dimethyl carbonate (30 ml) is heated under reflux for 6 hours with stirring. The reaction mixture is treated in a manner as in Reference Example 11 to give methyl 7,8-dimethyl-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate as a colorless oily product (1.3 g). This product (1.2 g) is dissolved in a mixture of methylene chloride (40 ml) and methanol (50 ml). To the solution is added sodium borohydride (0.3 g) in limited amounts, and the mixture is stirred. After addition of water, the reaction mixture is extracted with methylene chloride. The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. To the residue are added methanol (2 ml) and a 1N aqueous solution of sodium hydroxide (10 ml). The mixture is stirred at 60° C. for 15 minutes. To the reaction mixture are added water and ether and the mixture is shaken. Then the aqueous layer is separated. The aqueous layer is acidified with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. To the residue are added dioxane (8 ml) and concentrated hydrochloric acid (1 ml). The mixture is stirred at 100° C. for 40 minutes. To the reaction mixture is added water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried, and evaporated to dryness. The residue is recrystallized from ethyl acetate to afford 7,8-dimethyl-2,3-dihydro-1-benzoxepin-4-carboxylic acid as colorless needles (0.75 g), m.p. 266°-267° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.CN.C[CH2:17][N:18](C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:18][CH3:17])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNc1cc(C(=O)OC)nc(Cl)n1
Reaction time: 1 h

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g), methylamine hydrochloride (0.72 g) in CH2Cl2 (48 mL) at 0° C. was added Hunig's base (3.7 mL) dropwise, and the reaction mixture was stirred at ice bath for 1 h and then rt for 1 h. The solvent was removed in vacuo, and the white residue was purified directly by Biotage eluting with 40-600% EtOAc/Hexanes (1000 mL) followed by 90% CH2Cl2/10% MeOH (4 L) to give the title compound as a white solid (1.8 g). These fractions were combined and evaporated in vacuo. During the solvent removal, some white solid was formed. Several filtrations gave the title compound as a white solid (1.8 g, very white solid).). LC-MS (M+H)+=202.00
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:16])C.[NH4+]>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][NH:3][C:2]2=[O:16])=[CH:7][C:8]=1[F:13]
Reactant: CC(=O)[O-]
Reactant: Fc1cc2ccnc(Cl)c2cc1Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(F)c(Cl)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
41.13 g of 1,7-dichloro-6-fluoro-isoquinoline (6) were dissolved in 670 ml of acetic acid. After addition of 148.8 g of ammonium acetate, the solution was stirred at 100° C. After 3 h, the solvent was removed under reduced pressure and the residue was poured onto water. The aqueous phase was extracted three times with dichloromethane, the combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to dryness. The crude product was crystallized from ethyl acetate:heptane to yield 14.85 g of the desired product. Another 4.5 g could be obtained upon evaporation and silica gel chromatography of the mother liquor.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([N:8]=[N+:9]=[N-:10])[CH2:5]1)(O)=[O:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:8]([C@@H:6]1[CH2:7][C@H:4]([C:1]([Cl:14])=[O:2])[CH2:5]1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
A solution of cis-3-carboxycyclobutyl azide (1.86 g, 13.2 mmol) in dichloromethane (30 ml) was treated with oxalyl chloride (1.5 ml, 17.2 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (0.5-1 h) and the solvent was evaporated in vacuo leaving a yellow oil; 2.0 g, 95% ir (neat) νmax :2100 (N3) and 1785 cm-1 (C=O of acylchloride).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+:23]>CCO.O>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[O:12][N:11]=2)=[CH:8][CH:9]=1.[Na+:23]
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (1.7 g, 5.6 mmol) in EtOH/H2O (30 mL), 1 M NaOH (8.4 mL, 8.4 mmol) was added at RT. The mixture was stirred at RT for 1 h, and concentrated under reduced pressure to afford sodium 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (1.6 g, 96%) as a white solid, which was directly used for next reaction without further purification.