Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1.CNCCNC.[I-:27].[Na+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[I:27][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1
Reactant: [I-]
Reactant: C[C@@H](Oc1cc(Br)cc2ncccc12)[C@H]1CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(I)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 110 °C
Yield: 26.3 %

Procedure:
50 mg of Example 27 and 9 mg of copper (I) iodide were suspended in 300 μL dioxane under argon. 9.6 μL N,N′dimethylethylendiamine and 45 mg of sodium iodide were added and the mixture heated to 110° C. over weekend. The mixture was diluted with DCM and extracted with aqueous ammonia and water, the organic phase was subsequently concentrated in vacuo and the residual purified with HPLC (XbridgeC18; MeOH/water, TFA) to yield 15 mg yellow solid as Example 37.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.140 g, 0.241 mmol) and cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (0.064 g, 0.241 mmol) in N,N-dimethylformamide (10 mL) was added a 2.0 M solution of N,N′-dicyclohexylcarbodiimide in N,N-dimethylformamide (121 μL, 0.241 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.04 g, 0.0689 mmol, 28.6%). LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.2 [M+H+].
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11](Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:30][C@H:31]1[CH2:36][NH:35][C@@H:34]([CH3:37])[CH2:33][NH:32]1.N[C@H](C(N[C@H](C(O)=O)C)=O)C.O=C1NCCNC1=O>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:32]2[CH2:33][C@H:34]([CH3:37])[NH:35][CH2:36][C@@H:31]2[CH3:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: C[C@H]1CN[C@@H](C)CN1
Agent: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: O=C1NCCNC1=O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)N2C[C@H](C)NC[C@@H]2C)cc1
Yield: 22.1 %

Procedure:
A mixture of 15.65 g (36 mmol) of N,N-diethyl-4-(3-(t -butyldimethylsilyloxy)-α-chlorobenzyl)benzamide, prepared as described in Example 11, 7.22 g (65 mmol) of (+)-(2S,5S)-2,5-dimethylpiperazine, prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described by Jung and Rohloff (J. Org. Chem. 50, 4909-13 (1985)), and 3 mL of toluene was heated as in Example 1. The product was purified by chromatography on silica gel (Waters Prep 500 with dichloromethane containing 1% ethanol and 0.1% triethylamine) to give 4.06 g (22%) of N,N-diethyl-4-(3-(tert-butyldimethylsilyloxy)-α-((2S,5S)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide as a beige foam.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][NH2:40].Cl>N1C=CC=CC=1>[CH3:38][O:39][N:40]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:33][CH:34]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1
Temperature: 0 °C

Procedure:
A solution of the compound obtained in Step A (500 mg) and O-methylhydroxylamine hydrochloride (165 mg) in 15 ml of pyridine is heated at reflux for 3 hours. The reaction mixture is hydrolysed using 100 ml of ice-cold water, acidified using 6N HCl and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is then purified on silica gel, eluant AcOEt/PE 2/8, to yield the title compound in the form of a white oil (wax).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:19]([NH:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)s1
Reaction time: 20 h

Procedure:
To a solution of 8.6 g. of ethyl 5-amino-2-thiophenecarboxylate and 25 ml. of triethylamine in 100 ml. of methylene chloride is added dropwise 16.5 g. of palmitoyl chloride. The reaction mixture is stirred for 20 hours. Evaporation affords an oil. A methylene chloride solution of the oil is filtered and the filtrate passed through Magnesol. Removal of the solvent by evaporation yields a solid which is recrystallized from hexane. A second recrystallization from carbon tetrachloride affords the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]3[CH2:15][C:10]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)([CH2:11]3)[C:9]2=[O:25])=[CH:5][CH:4]=1.CCOCC>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]23[CH2:11][CH:12]([CH2:15]2)[C:13](=[O:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[C:9]3=[O:25])=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2C(=O)C3CC(c4ccc([N+](=O)[O-])cc4)(C3)C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)C3CC(c4ccc(N)cc4)(C3)C2=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 5.0 g of 3-(4-methoxybenzyl)-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 100 ml of ethyl acetate, hydrogenated in the presence of 1 g of 5% palladium-on-carbon and worked up. Melting point 147°-147.5° (from ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH3:21]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:19][CH2:20][CH3:21])[C:5]([OH:7])=[O:6]
Reactant: CCCI
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc(C(=O)O)cc1F
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A mixture of 2 g of 3-fluoro-4-hydroxybenzoic acid and 5.31 g of K2CO3 in 50 ml of acetonitrile is refluxed for 24 hours, 0.5 ml of 1-iodopropane is added and the refluxing is continued for 7 hours. After cooling to AT, the reaction mixture is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with EtOAc and the solvent is evaporated off under vacuum. The residue is taken up in 30 ml of EtOH, 5 ml of a concentrated NaOH solution are added, and the mixture is left to stir at 60° C. for 1 hour. The mixture is concentrated under vacuum, the residue is taken up with a 10% HCl solution, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 0.8 g of the expected compound is obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C:8]([C:10]1[C@@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][O:7][C:8]([C:10]1[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:12]([C:18]([O:20][CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46][O:41]2)=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCCCO2)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 36 mg of (4S)-5-(2-acetamidoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid in 0.5 ml of tetrahydrofuran were added 7.7 mg of p-toluenesulfonic acid, and then 0.24 ml of 3,4-dihydro-2-H-pyrane. The mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified using preparative TLC to obtain 18 mg of the objective compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][N:21]=3)[CH:16]=2)[S:11][CH2:10][CH2:9]1.O>C1COCC1>[CH3:7][C:8]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]3[N:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:29][CH:30]=3)[CH:16]=2)[S:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C#Cc3ccc(CO)cn3)cc21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To 3.0 ml of 1M lithium aluminum hydride (3.0 mmol) in THF, cooled to -78° C., was added dropwise over 5 min a solution of 2.0 g (5.9 mmol) of ethyl 6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)nicotinate in 5 ml of THF. The reaction mixture was stirred at -78° C. for 40 min and then treated with 2 ml of water. The mixture was warmed to room temperature and the organic layer was separated. The aqueous layer was extracted with 3×10 ml of ether. The organic extracts were combined and washed successively with 1×10 ml of dilute HCl, 3×10 ml of water and 1×15 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 50% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][C:8]#[N:9]>CCO.Cl.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][NH2:9])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C=CC#N)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCCN)cc1OC
Yield: 98.3 %

Procedure:
3,4-Dimethoxycinnamonitrile (5 g) was dissolved in a mixture of EtOH (100 mL) and conc. HCl (10 mL) and hydrogenated with 10% Pd/C (wet, Degussa Type E101, Aldrich) at 65 psi on a Parr shaker for 70 h. The reaction mixture was filtered over Celite and the filtrate was concentrated to remove most of the EtOH. The residue was extracted twice with Et2O (discarded) and then cooled with ice and made strongly basic with 10 M aq. NaOH solution. The basic aqueous layer was extracted with Et2O and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-(3,4-dimethoxyphenyl)propylamine (5.07 g) as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): δ=6.68-6.78 (m, 3H), 3.83 (s, 3H, OMe), 3.82 (s, 3H, OMe), 2.70 (t, J=7.0 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.70-1.75 (m, 2H), 1.17 (broad s, 2H, NH2).
Reaction SMILES: [F:1][C:2]([P:8]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(F)F)([F:7])[C:3]([F:6])([F:5])[F:4].C(=O)=[O:26].[PH5].[P:29]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])([C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38])[C:30]([C:33]([F:36])([F:35])[F:34])([F:32])[F:31].P(O)(C(C(F)(F)F)(F)F)(C(C(F)(F)F)(F)F)=O>>[F:1][C:2]([P:8](=[O:26])([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])([F:7])[C:3]([F:6])([F:5])[F:4].[P:29]([C:30]([C:33]([F:34])([F:35])[F:36])([F:31])[F:32])([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])[C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38]
Reactant: FC(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: O=C=O
Agent: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [PH5]
Product: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 6 h

Procedure:
12.01 g (28.0 mmol) of tris(pentafluoroethyl)difluorophosphorane, (C2F5)3PF2, are initially introduced in a 100 ml glass round-bottomed flask and warmed (120° C. oil-bath temperature). A cooled (−30° C. to −35° C.) intensive reflux condenser is connected downstream of the flask. A 250 ml glass round-bottomed flask containing dry ice is connected via a T-piece so that gaseous CO2 is forced through the phosphorane liquid. The liquid is stirred at 120° C. for 6 h. In this time, a total of about 400 g (9 mol) of CO2 are bubbled through the hot liquid. After 6 h, the condenser temperature is warmed to −5° C. The clear and colourless liquid remaining (4.53 g) consists of (C2F5)3PF2 (49%), (C2F5)3P═O (49%) and (C2F5)2P(O)OH (2%). Tris(pentafluoroethyl)phosphine oxide, (C2F5)3P═O, is isolated from the reaction mixture by distillation.
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:42]=[CH:43][CH:44]=1)[O:20][C:21]1[CH:27]=[C:26]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])[C:25]([F:41])=[CH:24][C:22]=1N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:22]1[CH:24]=[C:25]([F:41])[C:26]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])=[CH:27][C:21]=1[O:20][C:19]1[CH:18]=[C:17]([CH:44]=[CH:43][CH:42]=1)[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(N)cc2F)c1=O
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
0.34 g of isoamyl nitrite was added dropwise to a mixture of 1.5 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 0.57 g of copper (I) chloride, 1.17 g of copper (II) chloride, and 21 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.01 g of ([3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: B(Cl)(Cl)Cl.[CH:5]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C@H:22]3[C@H:27]([O:28]CC4C=CC=CC=4)[C@@H:26]([O:36]CC4C=CC=CC=4)[C@H:25]([O:44]CC4C=CC=CC=4)[C:24]([CH2:52][O:53]CC4C=CC=CC=4)=[CH:23]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1.CC1C(C)=C(C)C(C)=C(C)C=1.CO>C(Cl)Cl>[CH:5]1([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C@H:22]3[C@H:27]([OH:28])[C@@H:26]([OH:36])[C@H:25]([OH:44])[C:24]([CH2:52][OH:53])=[CH:23]3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1
Reactant: C1=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1Oc1ccccc1Cc1ccc(C2CC2)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: OCC1=C[C@@H](Oc2ccccc2Cc2ccc(C3CC3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
In a nitrogen stream, a boron trichloride 1.0 M methylene chloride solution (160 μL, 0.16 mmol) was added to a solution of 1-(4-cyclopropylphenyl)methyl-2-[(1R,4R,5S,6S)-4,5,6-tris-benzyloxy-3-(benzyloxymethyl)-cyclohex-2-enyloxy]benzene (12 mg, 0.016 mmol) and pentamethylbenzene (24 mg, 0.17 mmol) in methylene chloride (300 μL) at −78° C., and the mixture was stirred at the same temperature for 1.5 hours. After addition of methanol, the temperature of the resulting solution was raised to room temperature and the solvent was distilled under reduced pressure. The obtained residue was purified by preparative TLC [developing solution=methanol:methylene chloride (1:8)] to obtain the title compound (4.1 mg, 70%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>CN(C)C=O>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3cccnc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4cccnc4)cc3)CC2)ccc1O
Reaction time: 18 h
Yield: 14.6 %

Procedure:
To a stirred mixture of pyridine-3-sulfonic acid-[4-(4-oxo piperidin-1-yl)-phenyl]amide (which was obtained in Example 237) (0.94 g, 2.8 mmol), N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.70 g, 2.8 mmol) in dimethylformamide (10 mL) at room temperature was added sodium triacetoxyborohydride (0.72 g, 3.4 mmol) and glacial acid (0.18 mL, 3.1 mmol). The reaction was stirred under N2 atmosphere for 18 hours. The reaction mixture was poured onto 1:1 water/saturated sodium bicarbonate, extracted with ethyl acetate three times, dried over sodium sulfate and concentrated. The product was purified by flash silica gel chromatography eluting with 10% methanol in methylene chloride and finally with 20% methanol in methylene chloride to give the titled compound as a yellow solid (0.23 g, 15%); 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.45 (m, 2 H), 1.80–1.95(m, 2 H), 2.50–2.80(m, 5 H), 2.92(s, 3 H), 3.40–3.55(m, 2), 4.45–4.60(m, 1 H), 6.85–6.90(m, 5 H), 7.02(dd, J=8.3, 2.0 Hz, 1 H), 7.18(d, J=2.0 Hz, 1 H), 7.59(dd, J=7.4, 4.4 Hz, 1 H), 7.95–8.05(m, 2 H), 8.70–8.80(m, 2 H); MS (ES) m/z: 561.95 (MH+, 100%); HRMS Calcd. for C25H32N5O6S2(MH+): 562.1788. Found: 562.1774.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][CH:13]([CH3:15])[O-:14].[Na+]>C(O)(C)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([O:14][CH:13]([CH3:15])[CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)[O-]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(C(=O)O)cc(Cl)n1
Temperature: 150 °C
Yield: 54 %

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (1.26 g, 6.56 mmol) in isopropanol (20 mL) was added 27 mL (16.40 mmol) of freshly made sodium isopropoxide (0.61 M in isopropanol). This mixture was split evenly into four 20 mL microwave vials and each vial was heated under microwave irradiation at 150° C. for 10 min. The combined reaction solutions were eluted through a column of Dianion HP-20 PS resin eluting first with water followed by 100% acetonitrile to provide 770 mg (54%) of 2-chloro-6-isopropoxyisonicotinic acid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (d, 6H, J=6 Hz), 5.08-5.14 (m, 1H), 6.95 (s, 1H), 7.23 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[O:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]1[CH2:18][CH:19]=[C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][C:11]=2[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]3)[CH2:21][CH2:22]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(OC)c1nc2c(cc1C1=CCOCC1)CCCN2
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 1.0 g, 3.48 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g, 6.96 mmol) and Pd(PPh3)2Cl2 (0.24 g, 0.35 mmol) in aqueous Na2CO3 solution (2 M, 5.2 ml) and 1,2-dimethoxyethane (40 ml) was heated for 1.5 h at 100° C. under an atmosphere of argon. The cooled reaction mixture was then partitioned between aqueous NaHCO3 solution and EtOAc, the organic layer washed with brine, dried over MgSO4 and evaporated. The residue was then purified by normal phase chromatography using a 40 g RediSep® column, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were then combined and evaporated to give the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 1H), 6.52 (s, br, 1H), 5.54 (s, br, 1H), 5.11 (s, 1H), 4.17-4.14 (m, 2H), 3.77 (t, 2H), 3.28-3.21 (m, 2H), 3.25 (s, 6H), 2.65 (t, 2H), 2.26-2.20 (m, 2H), 1.80-1.72 (m, 2H). (UPLC-MS 3) tR 0.55 min; ESI-MS 291.2 [M+H]+.