Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCCN(CC2CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: C1CNCCN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.7 %

Procedure:
The resulting benzyl 4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) was dissolved in 50 mL of ethanol, 10% palladium-carbon (500 mg) was added, and the reaction mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. The palladium-carbon was removed by filtration, and the filtrate was evaporated to give the title compound (1.4 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CO>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:13]1[CH2:14][CH2:15][N:11]([C:8]2[C:7]3[CH:2]=[N:3][CH:4]=[CH:5][C:6]=3[S:10][CH:9]=2)[C:12]1=[O:23]
Reactant: Cc1ccncc1N1CCN(c2csc3ccnc(Cl)c23)C1=O
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccncc1N1CCN(c2csc3ccncc23)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
Activated Zinc (417 mg, 6.380 mmol) was added to a stirred solution of 1-(4-chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-136a: 220 mg, 0.6380 mmol) in acetic acid (10 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Aqueous NH3 solution was added to the concentrate and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 80 mg of the product (40.6% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[C:5]#N.OS(O)(=O)=O.O.[C:23]([OH:26])(=[O:25])C>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][C:23]([OH:26])=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
2,4-Bis(trifluoromethyl)benzonitrile (41.5 mmol, 10.51 g) was taken up in 100 mL acetic acid, 50 mL conc. H2SO4, and 20 mL water. This was heated to 120° C. for 3 h. The reaction was then diluted with 1 L ice water, and extracted with 2×300 mL ethyl acetate. The combined organics were washed with 2×200 mL water, dried with brine and Na2SO4, and evaporated under reduced pressure. The residue was taken up in a minimum of diethyl ether and crystallized by adding sufficient hexane to precipatate the product. The solid was collected to give 7.74 g of 2,4-bis(trifluoromethyl) phenyl acetic acid as white crystals, 68.5%. NMR 1H (CDCl3) δ 7.93 (s, 1H), 7.80 (d, J=7.9 Hz,1H), 7.55 (d, J=7.9 Hz, 1H), 3.94 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].O.C(=O)(O)[O-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>ClCCl>[OH:4][CH2:3][C:2]([NH:1][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
3.0 g of 2-amino-2-methylpropan-1-ol was dissolved in 100 mL of dichloromethane, and 100 mL of water and 8.4 g of sodium bicarbonate were then added. To this solution, 5.7 g of benzyl chloroformate was added dropwise, and the mixture was stirred at room temperature for 16 hours. After extraction with dichloromethane (100 mL×3), the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 7.6 g of the compound of interest as a colorless oil (86%).
Reaction SMILES: C1(C2CCC3C(=CC=C(OC4C=CC=CC=4N)C=3)O2)C=CC=CC=1.[N+:25]([C:28]1[CH:49]=[CH:48][CH:47]=[CH:46][C:29]=1[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][CH:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:34]2)([O-])=O>>[C:40]1([CH:35]2[CH2:34][C:33]3[C:37](=[CH:38][CH:39]=[C:31]([O:30][C:29]4[CH:46]=[CH:47][CH:48]=[CH:49][C:28]=4[NH2:25])[CH:32]=3)[CH2:36]2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CC(c1ccccc1)C2
Agent: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Product: Nc1ccccc1Oc1ccc2c(c1)CC(c1ccccc1)C2

Procedure:
2-(2-Phenylindan-5-yloxy)phenylamine was prepared as described for 2-(2-phenylchroman-6yloxy)-phenylamine in Example 29(b) using 170 mg of 5-(2-nitrophenoxy)-2-phenylindane. 1H-N (400 MHz, d6-DMSO): 7.32-7.27 (m, 4H), 7.23-7.16 (m, 2H), 6.92-6.87 (m, 1H), 6.81-6.71 (m, 4H), 6.56-6.53 (m, 1H), 4.85 (bs, 2H), 3.65 (k, 1H, J 8.3 Hz), 3.23 (dd, 2H, J 8.3, 15.5 Hz), 2.97-2.88 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[H-].[Na+].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:35]I.[NH4+].[Cl-]>CN(C)C=O.C(OC)(C)(C)C>[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:35][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](O)C1
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
200 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methyl-propionate are dissolved in 5 ml of dimethylformamide, and 20 mg of NaH (95%) are added. After 60 min of stirring at room temperature, 460 mg of 5-methyl-2-p-tolyloxazol-4-ylmethyl iodide in 1.5 ml of dimethylformamide are added at 0° C. The mixture is stirred at room temperature for 2 h. 10 ml of methyl tert-butyl ether and 10 ml of saturated NH4Cl solution are then added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether and the organic phases are dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 5/1->1/1). 200 mg of the crude tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionate are obtained as a yellow oil. C27H39NO5 (457), LCMS (ESI): 458 (MH+).
Reaction SMILES: Br[CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[CH2:7]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:31]C)[N:18]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:14]([NH2:33])[N:13]=1)[CH2:8][CH2:9][CH3:10].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CS(C)=O>[NH2:33][C:14]1[N:13]=[C:12]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])[N:20]=[C:19]2[C:15]=1[NH:16][C:17](=[O:31])[N:18]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4])[CH2:27][CH2:26]1
Reactant: CCC(Br)CC
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C(CC)CC)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
3-Bromopentane (0.1 mmol) was weighed into a tube and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine (0.452 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and heated at 50° C. for 18 hours. An additional portion of 3-bromopentane (15 μl) and DIPEA (401) was added and heating continued for a further 18 hours. Potassium carbonate (46 mg) was added and heating continued for a further 72 hours. DMSO (200 uL) was added and the resultant mixture filtered, the solution was purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was dissolved in 1:1 DMSO:MeOH and purified by MDAP (Method C) and the solvent was evaporated in vacuo using the Genevac. The material was redissolved in methanol (0.5 ml), and applied to a 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml), the solvent was removed to give the title compound (5.9 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].P([O-])([O-])([O-])=O>CC(C)=O>[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.7 %

Procedure:
Enantiomerically enriched (ee Renantiomer=60%) ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (5.2 g) was dissolved in 30 ml acetone and added to an aqueous 0.1 M phosphate buffer pH 7 (1.0 l). Protease 2A from Aspergillus oryzae (Fluka No: 82463; 0.51 units/mg) (13 g) was added and the mixture was stirred for 3 days at room temperature. The reaction mixture was extracted 4× with 200 ml TBME. After drying of the combined organic phases over Na2SO4and evaporation of the TBME, 4.3 g of ethyl (2R)-2-Ethoxy-3-(4-hydroxyphenyl)propanoate was obtained as an oil (CCE method 2: ee=100%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[N:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:21])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[Cl:27][C:28]1[C:37]([CH:38]=O)=[N:36][C:35]2[NH:34][C:33](=[O:40])[CH2:32][S:31][C:30]=2[CH:29]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:27][C:28]1[C:37]([CH2:38][NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:21])[CH2:5][CH2:4]2)=[N:36][C:35]2[NH:34][C:33](=[O:40])[CH2:32][S:31][C:30]=2[CH:29]=1
Reactant: NC1CCN(CCn2c(=O)ccc3ccncc32)CC1
Reactant: O=Cc1nc2c(cc1Cl)SCC(=O)N2
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CSc2cc(Cl)c(CNC3CCN(CCn4c(=O)ccc5ccncc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one hydrochloride in 3 mL of methanol, 0.15 mL of a 28% sodium methoxide/methanol solution and 15 μL of acetic acid were added. Thereto were added 51 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde and 0.20 g of molecular sieves 3A, and the mixture was stirred at room temperature for 30 minutes. Thereto was added 33 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1 hour 30 minutes. Thereto was added 51 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde, and the mixture was stirred at room temperature for 2 hours. The insoluble substance was filtered off, and chloroform and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The organic layer was separated, and washed sequentially with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol 10:1 to obtain 97 mg of 7-chloro-6-(((1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][C@@H:24]([CH3:30])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([C:25]([CH3:29])([CH3:28])[C@@H:24]([NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:30])#[N:27]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: C[C@H](N)C(C)(C)C#N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.10 g, 2.95 mmol), (S)-3-amino-2,2-dimethyl-butyronitrile hydrochloride (439 mg, 2.95 mmol), EDC (1.3 g, 6.8 mmol) and HOBt (1.15 g, 6.8 mmol). DMF (27 mL) was added followed by i-Pr2NEt (3.6 mL, 20.7 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with water and extracted with EtOAc. The organics were washed with 10% citric acid, sat'd NaHCO3, sat'd LiCl, and sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50-100% EtOAc/hexane) to give 1.32 g (96%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyano-1,2,2-trimethyl-ethyl)-amide as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13](=[CH2:14])[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([O:27][CH2:14]3)[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1C(Cc2ccc(Cl)cc2)CCCCC1(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCCCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of chloroform was dissolved 340 mg of 7-(4-chlorobenzyl)-2,2-dimethyl-1-methylenecycloheptane [Compound (III-3) in Table III], and then 450 mg of m-chloroperbenzoic acid was added to the mixture over 10 minutes and the mixture was stirred at room temperature for one hour. Next, 385 mg of calcium hydroxide was added and the mixture was stirred at room temperature for 10 minutes.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[C:7]2[C:8]3[CH:24]([C:25](=[O:27])[NH2:26])[CH2:23][CH2:22][C:9]=3[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:15]([N:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])[C:7]=2[C:8]2[CH:24]([C:25](=[O:27])[NH2:26])[CH2:23][CH2:22][C:9]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCC1C(N)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)C1CCc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1
Reaction time: 14 h
Yield: 96 %

Procedure:
A slurry of (4-Benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid methyl ester (24 mg; 0.06 mmol) in THF (2 mL) and MeOH (0.7 mL) was treated with 1N aqueous LiOH (0.1 mL). The mixture was stirred for 14 hrs and was concentrated in vacuo. Purification by reverse phase chromatography (Vydac C18column; 5% to 70% of 0.1% HCl/H2O in 0.1% HCl/CH3CN) afforded 21 mg (92%) (4-Benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, compound 8, Scheme 1, as a white solid. 1H NMR (CDCl3) δ 7.30–7.19 (m, 4H), 7.09 (d, J=7.3 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.87 (app t, J=7.8 Hz, 1H), 6.67 (br s, 1H), 6.42 (d, J=7.8 Hz, 1H), 5.25 (s, 2H), 4.66–4.51 (m, 2H), 3.85 (d, 7.8 Hz, 1H), 2.96–2.84 (m, 1H), 2.76–2.62 (m, 3H); IR (KBr) 3413, 1716, 1667, 1636, 1614, 1496, 1432, 1256, 1115, 721, 701 cm−1; FDMS, 365 (M+1); Anal calcd for C21H20N2O4.0.5 HCl: C, 64.92; H, 5.40; N, 7.32. Found: C, 64.75; H,5.65; N, 7.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1/[CH:22]=[CH:23]/[C:24](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:24](/[CH:23]=[CH:22]/[C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[N:16][C:5]=2[CH:4]=1
Reactant: O=C(Cl)/C=C/c1cccs1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1cccs1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(2-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>C1COCC1.CO.[Ni]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(N)c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-Benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline E-1.1′ (5.000 g; 15.319 mmol) is dissolved in THF (50.000 ml) and filled into a Büchi autoclave. RaNi (500.000 mg) is added and hydrogenated at 6 bar overnight (pressure after 16 h=0.5 bar). The autoclave is filled again with 6 bar H2 and stirred for 5 hours at rt. The reaction mixture is filtered through a plug of celite and HCl in dioxane (4 M, 4.000 ml; 16.000 mmol) is added. The filtrate is concentrated under reduced pressure to give a residue, which is dissolved in the smallest possible amount of MeOH and sonicated for few minutes. Precipitation of the product occurs and the product is filtered off. The product is washed with a very small amount of MeOH and 50 ml of isopropyl ether and then dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[CH3:30][S:31]([C:34]1[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].Cl>>[CH3:30][S:31]([C:34]1[CH:35]=[C:36]([NH:40][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:29])[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:33]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Agent: Cl
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 573.2 [(M+H)+]; mp 215° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=[CH2:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([CH:9]2[CH2:10][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ncc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CC1c1ncc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
A mixture of 0.485 g of 3,5-dichloro-2-vinylpyridine (0.0014 mol) and 0.15 ml of ethyl diazoacetate (0.00127 mol) are added dropwise to 5 ml of refluxing xylene. The reaction mixture is refluxed for thirty minutes and left at room temperature overnight. After concentration to dryness and purification on silica, 250 mg of essentially pure ethyl 2-(3,5-dichloropyridin-2-yl)cyclopropanecarboxylate (75%) are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]4)=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:24]([NH2:27])[CH2:25][CH3:26]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]4)=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:27][CH2:24][CH2:25][CH3:26])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc4ccccc4cc3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc3ccccc3cc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)naphth[2,3-d]oxazole (277 mg, 0.9 mmol) and propylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (250 mg, 80%). 1H NMR (DMSO) δ 9.37(t, 1H), 8.90(d, 1H), 8.38(s, 1H), 8.33(s, 1H), 8.26(dd, 1H), 8.11(m, 2H), 7.56(m, 1H), 7.11(d, 1H), 3.50(q, 2H), 1.76(m, 2H), 1.09(t, 3H).
Reaction SMILES: [C:1]1(=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17](OCC)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a cold (5° C.) solution of ethyl ({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate (190) (0.200 g, 0.53 mmol) in THF (10 mL) was added 1 M solution of LiAlH4 (1.3 mL, 2.5 mmol). The reaction mixture was stirred at that temperature for 0.5 h. Reaction mixture was quenched with EtOAc (5 mL) and stirred for an additional 10 min before pouring into 20% aqueous HCl (50 ml). The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organics washed with brine (1×25 ml), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using hexanes and EtOAc (4:1 to 3:2) as an eluent to afford 155 mg (86%) of compound 224 as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.04 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 4.03 (t, J=5.1 Hz, 2H), 3.86 (t, J=5.1 Hz, 2H), 2.32 (d, J=4.5 Hz, 4H), 1.60 (br s, 8H). LCMS (ESI): m/z 337 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:13]1[C:18](=[O:19])[C:17]([OH:20])=[CH:16][O:15][C:14]=1[CH2:21]Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:21][C:14]1[O:15][CH:16]=[C:17]([OH:20])[C:18](=[O:19])[CH:13]=1)=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1cc(=O)c(O)co1)c1cccc(O)c1
Yield: 54.9 %

Procedure:
By following the procedure of Example 1 by employing 1.39 g(10.1 mmole) of 3-hydroxybenzoic acid, 0.4 g (10.1 mmole) of sodium hydroxide and 1.46 g(9.1 mmole) of chlorokojic acid, there was obtained 1.31 g(55.1%) of 2-(3-hydroxybenzoyl) oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.