Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCCOC3)c2n1
Reaction time: 4 h

Procedure:
N2-Butyl-8-methoxy-9-[2-(tetrahydro-2H-pyran-3-yl)ethyl]-9H-purine-2,6-diamine (138 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 4 h the reaction mixture was stripped, quenched with water then made basic with saturated sodium hydrogen carbonate. The resulting solid was filtered, washed and dried to give the title compound, yield 105 mg.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([NH:7][C:8]([C@H:10]2[N:15]3[C:16](=[O:31])[C@@H:17]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH:19]=[CH:20][CH2:21][C@H:14]3[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:5][C:4](=[O:32])[O:3]1>CCOC(C)=O.[Pd]>[OH:1][CH:2]1[CH:6]([NH:7][C:8]([C@H:10]2[N:15]3[C:16](=[O:31])[C@@H:17]([NH:22][C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:18][CH2:19][CH2:20][CH2:21][C@H:14]3[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:5][C:4](=[O:32])[O:3]1
Reactant: O=C1CC(NC(=O)[C@@H]2CCC[C@@H]3CC=CC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CC(NC(=O)[C@@H]2CCC[C@@H]3CCCC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4S,7S,11aR)-7-benzoylamino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-amide, 46, is dissolved in EtOAc and treated with a catalytic amount of Pd/C. The resulting suspension is stirred at room temperature under a H2 atmosphere for 2 hours. The solution is filtered to remove the catalyst and concentrated in vacuo to afford the desired product
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O.C(=O)(O)[O-].[Na+]>[CH3:15][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:3](=[N:2][O:1][CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccnc(CCl)n1
Reactant: Cn1ccnc1C(=NO)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cn1ccnc1C(=NOCc1nccc(N)n1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-2-yl)-1-phenylmethanimine (3.50 g, 17.4 mmol) and 2-(chloromethyl)pyrimidin-4-amine (2.62 g, 18.3 mmol) in acetonitrile (120 mL) were added cesium carbonate (5.67 g, 17.4 mmol) and potassium iodide (289 mg, 1.74 mmol). After stirring 6 h at 60° C., overnight at room temperature, then again 8 h at 60° C., the reaction mixture was diluted with water (150 mL), sat. aq. sodium bicarbonate (50 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine as a foamy solid [4.80 g, yield 76%; HPLC/MS: m/z=309 (M+H); log P(Neutral)=1.42].
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.[CH2:27]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N#N>ClCCl>[CH2:27]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([CH:43]=[O:44])[CH2:39][CH2:38]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)C1CCC(CO)CC1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: N#N
Solvent: ClCCl
Product: O=CC1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
2,2,6,6-Tetramethylpiperidine 1-oxyl (309 mg, 1.98 mmol) and (diacetoxyiodo)benzene (7.01 g, 21.8 mmol) were added to a solution of 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (cis-trans=4:1 mixture) (4.91 g, 19.8 mmol) at 0° C. in an N2 atmosphere, and the mixture was stirred at 0° C. for one hour and at room temperature for seven hours. The reaction solution was diluted with dichloromethane (200 mL), and the organic layer was sequentially washed with a saturated aqueous sodium sulfite solution (100 mL), a saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-formyl-cyclohexanecarboxylic acid benzyl ester (cis-trans=4:1 mixture) as a colorless oily substance (4.44 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cc(OC)cc(OC)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (3.9 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (50 mL), 3,5-dimethoxyphenylboronic acid (10.0 g), copper acetate (10.0 g) and pyridine (8.9 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.0 g, 40%) as a pale-yellow oil.
Reaction SMILES: [I-].[Na+].[CH3:3][N:4]1[S:13](=[O:15])(=[O:14])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([OH:16])=[C:5]1[C:17]([NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:25]=1)=[O:18].[C:26](=[O:33])([O:31][CH3:32])[O:27][CH:28](Cl)[CH3:29].C(O)(C)C.[K+].[Br-]>>[CH3:32][O:31][C:26]([O:27][CH:28]([O:16][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:13](=[O:15])(=[O:14])[N:4]([CH3:3])[C:5]=1[C:17]([NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:25]=1)=[O:18])[CH3:29])=[O:33]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: COC(=O)OC(C)Cl
Agent: [Br-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: COC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the method of Example 6, using a reflux time of 1 hour prior to addition of a sodium iodide, piroxicam (2.00 g, 6.0 mmol) and alpha-chloroethyl methyl carbonate (2.50 g, 18.1 mmol) were converted to chromatographed title product as a yellow solid which was crystallized from isopropyl alcohol (660 mg, 1.5 mmol, 25.0%): mp 150°-151° C.; IR (KBr) 1757, 1677 cm-1 ; 1H NMR (CDCl3) delta 1.75 (d, J=6 Hz, 3H), 3.12 (s, 3H), 3.65 (s, 3H), 6.35 (q, J=6 Hz, 1H), 7.07-7.18 (m, 1H), 7.65-7.95 (m, 5H), 8.30-8.42 (m, 2H), 9.42 (br s, 1H); precise mass calcd for C19H19N3O7S m/e 433.0944, found 433.1004.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].N([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C)=C=O>>[CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:6]([C:5]([NH2:4])=[O:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCN=C=O
Agent: CN1CC(=O)NC1=O
Product: CCCCCCC(N)=O

Procedure:
1-Methylimidazolidine-2,4-dione (100 mg, 0.876 mmol) and 1-isocyanatohexane (133.8 mg, 1.05 mmol) were reacted in analogy to example 1. Yield: 43.2 mg (20%), M+H+: 242.15.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1COCC1.O>[CH3:9][C:5]1([CH3:10])[C:6](=[O:8])[C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:2]([CH3:1])[C:3]=2[O:4]1
Reactant: Cc1cccc(OC(C)(C)C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 2-(2,3-dimethylphenoxy)-2-methylpropionic acid obtained in Reference Example 36 (21.0 g, 101 mmol) in THF (200 mL) was added DMF (0.1 mL), and then to the mixture was added dropwise oxalyl chloride (10.6 mL, 121 mmol). The reaction solution was warmed to room temperature, stirred for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), to which was added aluminum chloride (32.3 g, 242 mmol) at −70° C. or lower, and then warmed to room temperature over 12 hours. The reaction solution was added to water with ice-cooling and dichloromethane was distilled off under reduced pressure, which was extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium hydrogen carbonate solution, water and a saturated brine, and then was dried over anhydrous sodium sulfate. The residue after distilling off the solvent under reduced pressure was crystallized from ethyl acetate-hexane to obtain 17.5 g (yield 71%) of the title compound. Melting point: 79-81° C. (methanol).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]#[CH:3].[C:10](=[O:13])([O-:12])[NH2:11]>>[C:4]1([CH2:1][C:2]#[C:3][C:6]2[CH:5]=[C:4]([CH2:1][CH2:2][CH2:3][NH:11][C:10](=[O:12])[O:13][C:4]([CH3:9])([CH3:5])[CH3:1])[CH:9]=[CH:8][CH:7]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CCc1ccccc1
Reactant: NC(=O)[O-]
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CCc2ccccc2)c1

Procedure:
Coupling of prop-2-ynylbenzene with bromide 57 was conducted following the method used in Example 22. Purification by flash chromatography (6% EtOAc-hexanes) gave tert-butyl 3-(3-(3-phenylprop-1-ynyl)phenyl)propylcarbamate as a brown oil. Yield (0.85 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.41-7.43 (m, 2H), 7.35 (t, J=8.0 Hz, 2H), 7.10-7.28 (m, 5H), 4.52 (br s, 1H), 3.84 (s, 2H), 3.14-3.16 (m, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.80 (quint, J=7.6 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][N:43]([CH2:46][C:47](O)=[O:48])[C:42](=[O:50])[N:41]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:47](=[O:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([O:36][CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])=[N:41][C:42]1=[O:50])[CH3:2]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Yield: 84.9 %

Procedure:
The title compound (2.99 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.90 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 11.00 (s, 1H), 8.86 (brs, 1H), 8.27 (d, 1H), 8.18 (d, 1H), 7.89 (d, 0.6H), 7.83 (d, 0.4H), 7.68˜7.61 (m, 2H), 7.45˜7.26 (m, 10H), 6.94 (t, 1H), 6.79 (s, 1H), 4.81 (s, 1.2H), 4.62 (s, 0.8H), 4.35 (s, 0.8H), 4.13 (q, 0.8H), 4.06 (s, 1.2H), 4.03 (q, 1.2H), 3.59 (t, 1.2H), 3.44˜3.39 (m, 2H), 3.21 (t, 0.8H), 1.19 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH2:9])=[N:6][CH:5]=[CH:4][N:3]=1.CC(O)=O.[N:14]([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:7]2[N:6]([N:14]=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=N[O-]
Reactant: NNc1nccnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nccn2nnnc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A 2 L round bottom flask was charged with 2-chloro-3-hydrazinylpyrazine (440 g, 3.0 mol) and CH3COOH (500 mL). To the above was added dropwise a solution of NaNO2 (220 g, 3.2 mol) in water (200 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the resulting crystalline solid was collected by filtration, washed with EtOH (200 mL), and dried to afford 350 g (73%) of the product as a red solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=CC=C[C:11]=2N=N1.[OH:28][CH:29]1[CH2:32][N:31]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=2)[CH2:30]1.CC(N)C.C(N(CC)C(C)C)(C)C>ClCCl>[OH:28][CH:29]1[CH2:30][N:31]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([NH:8][CH:12]([CH3:13])[CH3:11])=[O:39])=[CH:40][CH:41]=2)[CH2:32]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(N2CC(O)C2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.64 g, 10.5 mmol, from Aldrich) was added to a mixture of 4-(3-hydroxyazetidin-1-yl)benzoic acid (1.93 g, 10.0 mmol), 2-propanamine (4.26 mL, 50.0 mmol) and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) in dichloromethylene (10 mL). The mixture was stirred at room temperature for 2 h, and diluted with dichloromethane. The mixture was washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 0-50%) to afford the desired product (2.21 g, 94.3%). LCMS cacld. for C13H19N2O2 (M+1)+: m/z=235.1. Found: 235.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:34][CH2:33][CH2:32][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCN1CCCCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(1-piperidinyl)ethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.75 (1H, br), 10.70 (1H, br), 10.15 (1H, br), 8.20 (1H, m), 7.38-7.11 (5H, m), 4.01 (2H, s), 3.39 (2H, m), 2.38 (6H, m), 1.50 (4H, m), 1.39 (2H, m); ES +MS: 425 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:23]=4[F:31])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH2:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[NH:34][CH3:33])=[CH:24][C:23]=4[F:31])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(=O)O)cc4F)ncc3O2)CC1
Product: CNC(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)c(F)c1

Procedure:
The title compound is prepared from 4-[5-(4-carboxy-2-fluoro-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and methylamine following a procedure analogous to that described in Example 26. LC (method 7): tR=1.25 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[CH:15][C:14]=2[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:7]([Br:32])[CH:6]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][CH2:3][OH:2])[CH:6]=[C:7]([Br:32])[C:8]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[C:16]([O:22][CH3:23])=[CH:15][C:14]=1[CH:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(OC)cc2C(=O)c2ccccc2)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)c(Oc2c(Br)cc(CCO)cc2Br)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4-(2-benzoyl-5-isopropyl-4-methoxy-phenoxy)-3,5-dibromo-phenyl)-acetic acid methyl ester (100 mg, 0.17 mmol) in THF under N2 atmosphere was added DIBAL (0.87 ml, 5 eq) dropwise at 0° C. The reaction was stirred at 0° C. for 15 minutes and allowed to reach room temperature and stirred for another 2 h. The mixture was poured into ice, and the aqueous phase extracted with EtOAc and the combined organic layers were dried over MgSO4 and concentrated. Purification on silica gave 2-(3,5-dibromo-4-(2-(hydroxy-phenyl-methyl)-5-isopropyl-4-methoxy-phenoxy)-phenyl)-ethanol as a solid (mg, %). 1H NMR (CD3COCD3): d
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:23])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-chloro-3-(trifluoromethyl)benzoic acid (CAS RN 1737-36-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (30%). MS (ESI): m/z=405.10 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C2[N:23]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[C:14]([C:9]1([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:16])[NH2:23]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of N-Boc-1-amino-1-cyclopentane carboxylic acid (518 mg, 2.26 mmol) and HOBt hydrate (416 mg, 2.71 mmol) in DMF (5 mL), EDC (522 mg, 2.71 mmol) was added. After being stirred at room temperature for 1 h, conc. NH4OH (14 N, 0.900 mL, 12.6 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 1-carbamoylcyclopentylcarbamate (305 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6]1
Reactant: BrCCCC1=CCc2ccccc21
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: C1=C(CCCN2CCCCC2)c2ccccc2C1
Yield: 89 %

Procedure:
3-(3'-Bromopropyl)indene (94.8 g, 0.4 M) and piperidine (76 g,0.9 M) are dissolved in 400 ml toluene. The mixture is heated under reflux 2 hours. After cooling, a large amount of solid is removed by filtration and washed with ether. The combined filtrate and washes are concentrated in vacuo. The residue is dissolved in ether and filtered to remove a small amount of insoluble material. The ether is removed in vacuo and the product is distilled collecting a fraction of 87.3 g (89% yield) boiling 132°-153°/0.05 mm.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2cccc3c2CCC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 24.5 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (75 mg, 0.234 mmol) in acetonitrile (10 mL) was added potassium carbonate (96 mg, 0.702 mmol) and ethyl iodide (109 mg, 0.702 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 24%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([C:16](N(OC)C)=[O:17])=[CH:14][C:13]=1[S:24](=[O:27])(=[O:26])[NH2:25]>O1CCCC1>[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:14][C:13]=1[S:24]([NH2:25])(=[O:27])=[O:26]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2cccs2)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of thiophene (0.27 g, 3.20 mmol) dissolved in tetrahydrofuran (10 mL) at −78° C. under nitrogen is dropwisely added 1.6 M of n-butyllithium (2 mL, 3.40 mmol). The reaction mixture is stirred at −78° C. for 1 h then a solution 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (0.3 g, 1.08 mmol) in tetrahydrofuran (2 mL) is added slowly and the reaction mixture is allowed to warm to room temperature and stirred for 1 h. The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 0.059 g (18%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 8.33 (d, J=2 Hz, 1H), 8.15 (dd, J=4, 1 Hz, 1H), 8.05 (dd, J=8, 4 Hz, 1H), 7.85 (m, 4H), 7.35 (m, 1H). Analytics calculated for C11H8ClO3S2: C, 43.78; H, 2.67; N, 4.64. Found: C, 43.70; H, 2.61; N, 4.61. MS (m/z): 300.0 (M−1).