Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>CCO.O>[CH:7]1[CH:6]=[CH:5][C:3](=[O:4])/[C:2](=[CH:1]/[NH:12][CH2:11][CH2:10][NH:13]/[CH:1]=[C:2]2/[CH:8]=[CH:7][CH:6]=[CH:5][C:3]/2=[O:4])/[CH:8]=1
Reactant: O=Cc1ccccc1O
Reactant: NCCN
Solvent: CCO
Solvent: O
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of salicylaldehyde (24.42 g, 0.200 mole) in 80 ml of EtOh was added to a stirred solution of ethylenediamine (6.070 g, 0.100, olc) in a mixture of 50 ml EtOH and 50 ml of H2O over a period of 5 minutes. The reaction mixture was refluxed for 1 hour and stirred at room temperature overnight. The yellow crystalline product was separated by filtration and washed with 2×30 ml of cold 60% EtOh and air dried to yield 25.733 g (95.9%) of salen.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1>O.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:38])[C:34]([F:35])([F:36])[F:37])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: O=C(NC[C@H](NC(=O)C(F)(F)F)C(=O)O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC[C@H](NC(=O)C(F)(F)F)C(=O)O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
To a solution of N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-2(S)-trifluoroacetylamino-β-alanine trifluoroacetate in water (4 ml) was added Pd/C (10% dry, 16 mg) and the mixture was stirred at room temperature under hydrogen at atmospheric pressure for 4 hours. Catalyst was filtered off and filtrate was evaporated in vacuo to give N-[(R)-1-[3-(4-piperidyl)propanoyl]-3-piperidylcarbonyl]-2(S)-trifluoroacetylamino-β-alanine trifluoroacetate as a colorless oil (45 mg, 54.9%).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:16])[C:7](S(O)(=O)=O)=[CH:8][CH:9]=[CH:10][CH:11]=1.C1(C)C=CC=C(S(O)(=O)=O)C=1>C1(C)C=CC=CC=1>[C:6]1([CH3:16])[CH:7]=[CH:8][C:9]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:10][CH:11]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: O=S(=O)(O)O
Agent: Cc1cccc(S(=O)(=O)O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 26 %

Procedure:
Sulfuric acid (1.0 g, 10.2 mmol) was added to toluene (50.0 g) under the same conditions as Example 1. The analysis by HPLC showed 26% yield p-toluenesulfonic acid, 11% o-toluenesulfonic acid, and 1.3% m-toluenesulfonic acid (ratio p/o=2.4) for a total yield of 38.3%.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][N:6]1[N:10]=[CH:9][CH:8]=[N:7]1)C.O.[NH2:13][NH2:14]>C(O)C>[N:10]1[N:6]([CH2:5][C:4]([NH:13][NH2:14])=[O:11])[N:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)Cn1nccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cn1nccn1
Temperature: 25 °C
Yield: 68 %

Procedure:
As described for example 112a, [1,2,3]triazol-2-yl-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture heated under reflux for 3 h. The mixture was cooled to rt and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 68%). MS: m/e=141.1 [M]+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[NH:11][C:10]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:25][C:26]#[N:27]>CN(C)C=O>[C:26]([CH2:25][N:11]1[C:12]2[C:17](=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:27]
Reactant: N#CCCl
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (from 7.2 gms., 0.15 mole 50% sodium hydride dispersed in mineral oil) in 125 ml fresh dimethyl formamide (DMF) is added ethyl 3-phenyl-5-chloroindole-2-carboxylate (45 gms, 0.15 mole), as a dry powder, in portions. The reaction is exothermic and requires a water bath to maintain the temperature between 45°-50° C. After stirring 15-20 minutes (at 35° C), chloroacetonitrile (12 grams, 0.15 mole) in 25 ml DMF is added slowly. The temperature rises to 45° C and the mixture is stirred overnight at ambient temperature. The mixture is then transferred to a one liter beaker and 500 ml of ice-water is added slowly. After 15-20 minutes the product is filtered off, washed well with water, and dried on a Buchner funnel. After recrystallization from ethanol the product gives a m.p. of 117°-19° C. There is obtained a total of 46 grams (90.2%), of sufficient purity for the next step. A sample is recrystallized from aqueous ethanol, washed with water and vacuum dried, m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:10]=1.Cl.Cl.[CH3:30][C:31]1[N:35]=[C:34]([C@H:36]([NH2:38])[CH3:37])[O:33][N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([NH:38][C@@H:36]([C:34]3[O:33][N:32]=[C:31]([CH3:30])[N:35]=3)[CH3:37])=[O:20])=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:10]=1
Reactant: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)O)cc32)cc1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
3-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (30.0 mg, 0.040 mmol, with 6 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (12.5 mg, 0.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 0.085 mmol), 1-hydroxy-7-azabenzotriazole (3.4 mg, 0.025 mmol), and N-methylmorpholine (20 μl, 0.182 mmol) were dissolved in N,N-dimethylformamide (500 μl) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 30 min. The reaction was stopped and quenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL). The crude reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%), to afford the title compound (16.3 mg, 0.023 mmol, 58.2% yield) as a white solid. HRMS [M+1]=474.1739. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H); 7.77 (d, J=8.6 Hz, 1H); 7.66 (d, J=8.2 Hz, 2H); 7.61 (dd, J=8.5, 1.4 Hz, 1H); 7.48-7.40 (m, 1H); 7.38 (d, J=8.1 Hz, 2H); 7.10 (m, 2H); 6.79 (d, J=7.7 Hz, 1H); 5.62 (m, 1H); 2.46 (s, 3H); 2.41 (s, 3H); 1.73 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:18][CH:17]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Subject 6.5 g. (33.0 mmoles) of 1-adamantane carboxylic acid chloride, 4.0 g. (33.0 mmoles) of p-anisidine and 10.0 ml. of triethylamine to the process of Example 11 and crystallize the residue obtained thereby from chloroform to yield the title product, m.p. 181°-184°C.
Reaction SMILES: [K].CCO.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6](OCC)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:32])[C:20]([N+:29]([O-])=O)=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=1>CCOCC>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[CH:18]=[C:19]2[C:20]=1[NH:29][C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])=[CH:32]2
Reactant: COc1cc(C)c([N+](=O)[O-])c(OCCN(C)C)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OC)cc(OCCN(C)C)c2[nH]1
Temperature: 100 °C
Reaction time: 115 h
Yield: 18.2 %

Procedure:
A suspension of potassium (0.308 g, 7.87 mmol) in xylenes (6 mL) was heated to 100° C. and stirred rapidly as it was allowed to cool. The xylenes were removed and the potassium was washed with Et2O (×3) and covered with Et2O (10 mL). The mixture was treated with absolute EtOH (1.30 mL, 22.2 mmol) and stirred at reflux until the potassium had dissolved (3 h). The cooled mixture was treated with diethyl oxalate (1.07 mL, 7.87 mmol) then with a solution of the above nitrotoluene (2.00 g, 7.87 mmol) in dry Et2O (5 mL). After 115 h, the dark red precipitate was removed by filtration and washed with Et2O. The red solid (1.189 g) was dissolved in absolute EtOH (45 mL), acidified with AcOH (0.78 mL), and hydrogenated over Pd/C (10%, 0.44 g) at 1 atm H2 for 8 h. The mixture was filtered through Celite, concentrated, diluted with 0.2 M aqueous Na2CO3 (100 mL), and extracted with EtOAc (×4). The combined extracts were washed with water (×2), dried (Na2SO4), evaporated and purified by flash chromatography (2% Et3N/EtOAc) to give ethyl 7-[2-(dimethylamino)-ethoxy]-5-methoxyindole-2-carboxylate as a clear oil (0.44 g, 18%). 1H NMR (CDCl3) δ 10.93 (br s, 1 H, NH), 7.09 (d, J=2.1 Hz, 1 H, H-3), 6.67 (d, J=2.0 Hz, 1 H, H-4), 6.43 (d, J=2.0 Hz, 1 H, H-6), 4.38 (q, J=7.0 Hz, 2 H, OCH2CH3), 4.16 (t, J=6.5 Hz, 2 H, OCH2CH2N), 3.88 (s, 3 H, OCH3), 2.79 (t, J=7.0 Hz, 2 H, NCH2), 2.37 (s, 6 H, N(CH3)2), 1.40 (t, J=6.5 Hz, 3 H, OCH2CH3); 13C NMR δ 161.9 (CO2), 155.0, 146.0, 128.1, 127.7, 124.9 (C-2, 3a, 5, 7, 7a), 108.1 (C-3), 99.1 (C-4), 94.6 (C-6), 65.9 (OCH2CH2N), 60.6 (OCH2CH3), 58.3 (NCH2), 55.6 (OCH3), 45.1 (N(CH3)2), 14.4 (OCH2CH3). Calc for C16H22N2O4, M+306.1580. Found, 306.1577. Starting material (0.77 g, 39%) was recovered from the ethereal washes by extraction into acid, basification, and extraction with Et2O.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:36](F)(F)F)=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4CCN(C5C=C(C=CC=5)C(O)=O)CC4)=CC=3)=O)N=2)C=CC=CC=1.N1CCC(C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3CC)=O)=CC=2)CC1.C(OC(=O)C1C=CC(Br)=CC=1)(C)(C)C>>[CH2:36]([C:9]1[O:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)=[O:13])[CH3:40]
Reactant: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Reactant: O=C(O)c1cccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)c1
Agent: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
With the same method used for the preparation of 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid, 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid was prepared from 2-phenyl-5-ethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 4-bromobenzoic acid tert-butyl ester. LC-MS for C30H29N3O4 (m/e) calcd 495, obsd 496 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[NH2:77])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[NH:77][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:30])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA (110 uL, 0.62 mmol) and 2-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 71 mg.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCOCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH:34]1[C:39]([CH:40]=O)=[CH:38][C:37]2[O:42][CH2:43][O:44][C:36]=2[CH:35]=1>CCCCCC>[O:44]1[C:36]2[CH:35]=[CH:34][C:39]([CH:40]=[C:2]([CH3:3])[CH3:1])=[CH:38][C:37]=2[O:42][CH2:43]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)=Cc1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
62.5 ml of a 1.6 M solution of butyllithium in hexane was added to 500 ml of anhydrous ether. 38.5 g of isopropyltriphenylphosphonium bromide was added thereto in a nitrogen gas stream and the mixture was stirred for 4 h. 18 g of piperonal was added to the reaction mixture and the resulting mixture was stirred for 5.5 h and then filtered. The filtrate was washed with 1 l of ether, concentrated under reduced pressure and purified according to silica gel column chromatography (hexane/ethyl acetate=10:1) to obtain 13.1 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=3)[S:4][C:3]=1[C:19]([NH2:21])=[O:20].[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:18][O:17][C:9]1[C:10]([O:15][CH3:16])=[CH:11][C:12]2[CH:13]=[C:14]3[C:2]4[N:1]=[N:22][NH:21][C:19](=[O:20])[C:3]=4[S:4][C:5]3=[N:6][C:7]=2[CH:8]=1
Reactant: COc1cc2cc3c(N)c(C(N)=O)sc3nc2cc1OC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2cc3c(nc2cc1OC)sc1c(=O)[nH]nnc13
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of 3-amino-6,7-dimethoxythieno[2,3-b]quinoline-2-carboxamide in 1.5 liters of glacial acetic acid was added dropwise a solution of 4.0 g of sodium nitrite in 20 ml of water. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then evaporated from the reaction mixture under reduced pressure to concentrate it to a volume of 300 ml. The solid which formed was separated by filtration to give 8,9-dimethoxy-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one. A small portion of this product was washed with hot tetrahydrofuran to give an off-white solid melting at greater than 230° C. with decomposition. The product obtained has the following structural formula ##STR3##
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[BH4-].[Na+]>CC(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][N:19]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Fc1ccc(-c2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Benzyl bromide (52.4 mL, 441 mmol) was added to a solution of 4-(4-fluorophenyl)pyridine (Description 14, 50.87 g, 294 mmol) in acetone (500 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled to room temperature and the solid was collected, washed with acetone and diethyl ether and dried in vacuo. The solid was dissolved in methanol (400 mL) and water (100 mL), cooled to 0° C. and sodium borohydride (20.6 g, 542 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, then heated to reflux for 18 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Dichloromethane (300 mL) and water (200 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light brown oil (61.5 g, 78%). m/z (ES+) 268 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[N:9]([CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:19][CH2:18]1)[C:8]2=[O:32].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:13][C:10]2[N:9]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:21][CH2:22]3)[C:8](=[O:32])[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[N:11]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(C)nc12
Solvent: CC(=O)O
Product: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(C=Cc3ccc(Cl)cc3)nc12

Procedure:
A solution of the product from Step C (144 mg, 0.33 mmol) and 4-chlorobenzaldehyde (46 mg, 0.33 mmol) in acetic acid (15 mL) was heated at 120° C. for 17 h. The reaction mixture was concentrated under vacuum and the residue was diluted with CHCl3. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. Purification via SiO2-gel chromatography using EtOAc/NEt3 (10:1) yielded the desired product. API-MS: 563 (M+1). 1H NMR (300 MHz, CDCl3): d 8.0 (d, 2 H), 7.8 (d, 1 H), 7.5 (d, 2 H), 7.38 (m, 3 H), 7.15 (d, 1 H), 7.0 (d, 2 H), 4.1 (t, 2 H), 4.0 (s, 3 H), 2.85 (m), 2.3 (m), 1.9-1.2 (m).
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].F[B-](F)(F)F.[C:39]([PH+](C(C)(C)C)C(C)(C)C)(C)(C)[CH3:40]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:31]([CH:39]=[CH2:40])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33]
Reactant: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Agent: [Pd]
Agent: F[B-](F)(F)F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N

Procedure:
To a degassed solution of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1k) (0.60 g, 1 mmol) in anhydrous dioxane (4 mL) was added under argon Cs2CO3 (0.665 g, 2.0 mmol), 2,4,6-trivinyl-cyclotriboroxane pyridine complex (0.365 g, 1.5 mmol) and tri-tert-butyl-phosphonium tetrafluoroborate (0.044 g, 0.15 mmol) in dioxane was added under argon the Pd2(dba)3 (0.028 g, 0.03 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after flash-chromatography on silica gel (hexane-EtOAc 3:1 to 2:1) and crystallization from CH2Cl2-hexane as white crystals: HPLC RtA=2.22 min; ESIMS [M+NH4]+=504.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[CH:11][C:10]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([O:16][C:33]([C:32]([CH3:37])([CH3:36])[CH3:31])=[O:34])=[CH:11][C:10]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1cc(O)c(O)cc1NC(=O)c1sc2ccccc2c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1cc(NC(=O)c2sc3ccccc3c2Cl)c(C(=O)Nc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To a solution of N-phenyl-2-[((3-chlorobenzo(b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide (0.09 g, 0.21 mmol) in CH2Cl2 (1 mL) and pyridine (1 mL) at 0° C. was added trimethylacetyl chloride (0.027 mL, 0.22 mmol). The solution was allowed to warm to ambient temperature with stirring. After 16 hours, the reaction mixture was partitioned between ethyl acetate and dilute HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel to afford 0.038 g (40% yield) of N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxy4-((1,1-dimethylethyl)carbonyl)oxybenzamide as a white solid; NMR(DMSO-d6) 12.2 (s, 1), 10.8 (s, 1), 10.4 (s, 1), 8.3 (s, 1), 8.2 (d, 1), 8.0 (d, 1), 7.6-7.7 (m, 4), 7.4 (t, 1), 1.3 (s, 9) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH:24]=1)CCC>>[O:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:23]([C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)=[CH:24]1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1coc2ccccc12
Product: c1ccc2c(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)coc2c1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 4 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 3-tri-n-butylstannylbenzofuran. The title compound was obtained as a colourless solid; m/e 333 (MH+).