Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[I-].[Na+].[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])(=[O:11])[CH3:10].[H-].[Na+]>CN(C)C=O.O>[C:9]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][O:5][CH3:6])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: COCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
949 mg of 1-chloro-3-methoxypropane and 1.30 g of sodium iodide were dissolved in 20 ml of dimethylformamide under argon atmosphere and the mixture was stirred at 90° C. for 2 hours. The reaction solution was cooled on ice and 1.51 g (4.35mmol) of Compound 27 obtained in Example 27 and 89 mg of sodium hydride (60% oil dispersion) were added thereto. The mixture was stirred at room temperature for 1 hour, 943 mg of 1-chloro-3-methoxypropane and 191 mg of sodium hydride (60% oil dispersion) were added, the temperature was raised to 60° C. and the mixture was stirred for 2 days. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 1.18 g (65%) of 2-[4-[N-acetyl-N-(3-methoxypropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20](=O)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:17])[O:18][CH2:19][C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)OCC(=O)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccccc2)cc1
Yield: 10.2 %

Procedure:
To a stirred solution of 2-oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate (1.8 g, 0.004 mol) in acetonitrile (50 mL) was added triethylamine (10 mL, 0.07 mol) under an inert atmosphere. The reaction mixture was then refluxed for 2 h, concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude product. The crude material was purified via silica gel column chromatography to afford 3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (140 mg, 8%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[O:17][CH:18]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[O:17][CH:18]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCc1ccccc1CN1CCC[C@@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Agent: [Li]
Product: O=C(O)CCc1ccccc1CN1CCCC1c1nc(C(=O)NCCCCC2CCCCC2)co1

Procedure:
(R)-2-[[2-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-1-pyrrolidinyl]methyl]benzenepropanoic acid, monolithium salt;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br-:7].[Br:8][CH2:9][CH2:10][CH2:11][P+:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Br-:8].[CH3:1][N:2]1[CH:6]=[CH:5][N+:4]([CH2:9][CH2:10][CH2:11][P+:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3]1.[Br-:7]
Reactant: Cn1ccnc1
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCO
Product: Cn1cc[n+](CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 32 %

Procedure:
1-Methyl-3-(3-(triphenylphosphonio)propyl)-1H-imidazol-3-ium bromide was synthesized by refluxing the mixture of 1-methyl-1H-imidazole and (3-bromopropyl)triphenylphosphonium bromide (1:1) in ethanol for 12 h; after cooling down, the solvent was removed and the crude product was washed with ethyl acetate. Then the white product was treated with silver (I) oxide in CH2Cl2 for 12 h, and the crude Ag—NHC product was filtered and washed with CH2Cl2 and then with diethyl ether, and was used for the next step directly. The procedure for the synthesis of 3 is similar to that for 1. Total yield 32%; 1H NMR (400 MHz, CD3CN, 25° C.): δ=8.21 (t, J=8.0 Hz, 1H), 7.82 (m, 3H), 7.69-7.72 (m, 3H), 7.66 (d, J=2.0 Hz, 1H), 7.55-7.63 (m, 12H), 7.17 (d, J=0.9 Hz, 2H), 6.98 (d, J=0.9 Hz, 2H), 4.57 (t, J=7.1 Hz, 2H), 3.94 (s, 3H), 3.27 (m, 2H), 2.11 (m, 2H); FAB-MS: m/z 940 [M−OTf]+; Elemental Analysis calcd (%) for C38H33AuF6N7O6PS2.H2O: C, 41.20; H, 3.18; N, 8.85; found: C, 41.25; H, 3.29; N, 8.72.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:21][CH3:22])[CH:20]=1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:16]=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 100.4 %

Procedure:
A solution of 1-tert-butyl 1-piperazinecarboxylate (Sigma Aldrich, 3.37 g, 18.12 mmol), 5-fluoro-2-nitroanisole (Oakwood Products, West Columbia, S.C., 3.10 g, 18.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.31 mL, 36.2 mmol) in DMSO (11 mL) in a 20 mL glass microwave tube was sealed and heated in a heating block at 95° C. overnight (20 h). Upon cooling, the reaction mixture crystallized to a yellow solid. It was diluted with 150 mL of EtOAc, washed sequentially with 20 mL of water, 20 mL of NaHCO3 and brine (20 mL). The organic solution was dried over MgSO4 and concentrated affording tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (6.14 g, 18.20 mmol, 99% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 359.9 (M+Na)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.96 (1H, d, J=9.2 Hz), 6.59 (1H, dd, J=9.4, 2.5 Hz), 6.55 (1H, d, J=2.3 Hz), 3.97 (3H, s), 3.56-3.65 (4H, 3.45-3.52 (4H, m), 1.51 (9H, s). Pd/C (10 wt. %, dry basis, wet activated, 284 mm, 0.267 mmol) and tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (600 mg, 1.78 mmol) were treated with EtOH (30 mL) and allowed to stir under an atmosphere of hydrogen (balloon) for 23 h. The reaction mixture was filtered through an acrodisc (0.20 um), the resulting purple solution was then concentrated on the rotovap and then under vacuum overnight affording tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (539 mg, 1.76 mmol, 99% yield) as a purple film. m/z (ESI, +ve ion) 307.0/309.0 (M+H)+. 1H NMR (400 MHz, MeOH) δ ppm 6.71 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=2.3 Hz), 6.46 (1H, dd, J=8.3, 2.4 Hz), 3.85 (3H, s), 3.51-3.61 (4H, m), 2.92-3.02 (4H, m), 1.47-1.52 (9H, s).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[O:24][CH2:23][C@@H:21]([OH:22])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:12](=[O:25])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(O)CC>CN(C)C=O.N1C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[O:24][CH2:23][C@@H:21]([OH:22])[C@@H:19]([OH:20])[C@H:17]2[O:18][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12](=[O:25])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCCO
Product: O=C(Nc1ccn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2OC(=O)c2ccccc2)c(=O)n1)c1ccccc1
Temperature: 124 °C
Reaction time: 8 h

Procedure:
54.0 g (0.155 mol) of N4-benzoyl-1-(β-D-ribopyranosyl)cytosine 1 were dissolved in 830 ml of dimethylformamide (DMF) and 1.5 l of pyridine (both solvents dried and stored over molecular sieve 3 Å) with warming to 124° C. 23.0 g (0.163 mol; 1.05 eq.) of BzCl, dissolved in 210 ml of pyridine, were added dropwise at −58° to −63° C. in the course of 3.5 h. The batch was stirred overnight in a cooling bath. 90.3 g (1.5 mol; 10 eq.) of n-propanol were stirred in and the batch was concentrated at 40° C. in a high vacuum. Pyridine residues were removed by twice adding 150 ml of toluene and concentrating again. 124.3 g of residue were dissolved in 500 ml of CH2Cl2, extracted twice by stirring with 300 ml of half-concentrated NaHCO3 solution each time, and the precipitated solid was filtered off and dried: 60.7 g of residue. The CH2Cl2 phase was concentrated: 25.0 g. Separate chromatography on silica gel 60 (40×10 cm) with gradients (AcOEt/isohexane, 4:1, then pure AcOEt, then AcOET/MeOH, 19:1 to 2:1) yielded (TLC (silica gel, AcOET)):
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:34]([O:36][C:37](=[O:48])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[NH2:39])[CH3:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:34]([O:36][C:37](=[O:48])[C@@H:38]([NH:39][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=1)[CH3:35]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 59.5 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 5, Step E (0.240 g, 0.563 mmol), L-tyrosine ethyl ester hydrochloride (0.157 g, 0.676 mmol), 1-hydroxy benzotriazole (0.084 g, 0.619 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.119 g, 0.619 mmol) were combined in amine-free N,N-dimethylformamide (2.25 mL), followed by the addition of N,N-diisopropylethylamine (0.294 mL, 1.69 mmol). The reaction was stirred at room temperature for 36 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane, followed by precipitation from diethyl ether with petroleum ether, to afford 0.207 g of the title compound as a white solid.
Reaction SMILES: C(O)C.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.O.C1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)=[CH:20][CH:19]=2)=[CH:27][C:26]=1[F:32]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Reactant: Fc1cc(I)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(Br)c(F)c3)cc2)CC1

Procedure:
First, 100 ml of ethanol containing 11.89 g of 4-(trans-4-pentylcyclohexyl)phenylboronic acid dissolved therein, 100 ml of benzene containing 10.0 g of 1-bromo-2-fluoro-4-iodobenzene dissolved therein, 33.2 ml of a sodium carbonate aqueous solution with a concentration of 2.0 mol/l, and 0.96 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 500 ml flask, and stirred under reflux for 16 hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:hexane) and recrystallized from acetone, to obtain 11.6 g (Y: 86.8%) of 4-bromo-3-fluoro-4′-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 100.0% as measured by GC.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=2)[C:7](=[O:19])[NH:6][C:5]1=[O:20].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>CN(C)C=O>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34]/[CH:3]=[C:4]3\[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]4[C:13]\3=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:10][CH:9]=4)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-n5cccc5)cc43)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione, (100 mg, 0.3727 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (71.3 mg, 0.3727 mmol) in 1 mL of N,N-dimethylformamide is heated at 100° C. for 0.5 h. After the solvent is evaporated, ether is added to the residue. The precipitate is collected, and washed with ether to give 122 mg (77%) of light brown solid mp 239-240° C.; HRMS (ESI) m/z calcd for C25H25N5O2 428.20811. found 428.20865 (M+H)+1, Analysis for C25H25N5O2 (0.6H2O), Calcd: C, 68.51; H, 6.02; N, 15.98. Found: C, 68.67; H, 5.85; N, 15.62.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:16][O:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][C@@H:29]([CH3:32])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:32][C@@H:29]([CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:15][CH2:16][C@H:17]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:18][O:19]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC[C@H](C)CCCBr
Reactant: C=CCCCC1COC(c2ccc(-c3ccc(O)cc3)cc2)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCC[C@H]1CO[C@H](c2ccc(-c3ccc(OCCC[C@@H](C)CC)cc3)cc2)OC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 0.9 g of 2-(4'-hydroxy-4-biphenylyl)-5-(4-pentenyl)-m-dioxane and 1.25 g of (S)-1-bromo-4-methylhexane in 25 ml of N,N-dimethylformamide was treated with 1.2 g of finely powdered potassium carbonate and the mixture was stirred overnight in an oil bath of 60° C. The suspension was suction filtered and the filtrate was concentrated in a vacuum. A solution of the residue in diethyl ether was washed twice with water, dried over sodium sulphate and concentrated. Chromatography of the crude product on 40 g of silica gel with hexane/ethyl acetate (vol. 23:2) and two-fold recrystallization from ethyl acetate gave pure (S)-trans-2-[4'-(4-methylhexyloxy)-4-biphenylyl]-5-(4-pentenyl)-m-dioxane; phase transition (S-S) 99.5° C., phase transition (S-SC *) 127° C., phase transition (SC *-Ch) 130° C., cl.p. (Ch-I) 148° C.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[N:21]=[CH:20][C:19]([NH:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(F)cc3)nc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2ccc(-c3ccc(F)cc3)nc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
2-{[4-(2-{[6-(4-Fluorophenyl)pyridin-3-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (270 mg) synthesized in Example 259-1 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (183 mg) as a white solid.
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[NH2:6][C@H:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:8]([OH:10])=[O:9]>CO>[ClH:4].[CH3:1][O:9][C:8](=[O:10])[C@H:7]([NH2:6])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N[C@@H](C(=O)O)C1CCCCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)C1CCCCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of acetyl chloride (0.5 mL, 7.04 mmol) in MeOH (10 mL) at 0° C. is added (R)-amino-cyclohexyl-acetic acid hydrochloride (1.0 g, 5.16 mmol). The mixture is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature and concentrated. The resulting residue is triturated with Et2O to afford the title compound (1.0 g, 93%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:9]=[C:8]2[CH2:24][CH2:25][N:26]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:2][CH3:3]>CCO.O.NN>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11]([N:10]([Si:14]([CH:21]([CH3:22])[CH3:23])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:9]=[C:8]2[CH2:24][CH2:25][NH2:26])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCOc1ccc2c(c1)c(CCN)cn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Combine 2-(2-(5-propoxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione (416 mg, 0.8 mmol) in 20 mL EtOH and 1 mL hydrazine hydrate. Reflux for 3 hours, filter through celite and concentrate to residue. Dissolve the residue in 10 mL MeOH and load onto a 12 g SCX ion exchange cartridge and rinse sequentially with MeOH, DMF, then MeOH. Elute the product with 2 M NH3 in MeOH to give the title compound as an oil: ISMS 375 (M+1); 1H NMR (CDCl3) 7.34-7.32 (d, 1H), 7.02 (s, 1H), 7.00-6.99 (d, 1H), 6.80-6.77 (m, 1H), 3.97-3.94 (m, 2H), 3.01-2.98 (m, 2H), 2.86-2.83 (m, 2H), 1.88-1.76 (m, 2H), 1.70-1.58 (m, 3H), 1.3 (bs, 2H), 1.14-1.08 (m, 18H), 1.06-1.02 (t, 3H).
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]C)=[O:25])[CH2:19][CH2:18]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1>Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][CH2:22]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CN1CCC(Nc2nc(-c3ccc(C=NN)cc3)cs2)CC1
Agent: Cl
Product: NN=Cc1ccc(-c2csc(NC3CCN(CC(=O)O)CC3)n2)cc1
Yield: 96 %

Procedure:
1 g of methyl (4-{4-[4-(aminoiminomethyl)phenyl]-1,3-thiazol-2-ylamino}piperid-1-yl)acetate hydrochloride (EXAMPLE 1) is added to 20 ml of 6N hydrochloric acid and the reaction mixture is heated under reflux for 5 hours. The mixture is evaporated to dryness and the residue is crystallized from acetone to give white crystals which melt at 216° C.; yield: 96%.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.O.[C:36]([OH:46])(=[O:45])[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:36]([O-:46])(=[O:45])[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]
Reactant: O=C(O)C(O)c1ccccc1
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])C(O)c1ccccc1

Procedure:
A suitable reactor is charged with acetone (38 mL). The acetone solution is sequentially charged with carvedilol (11.08 grams) and water (8 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution, 1N Mandelic acid in methanol (1 Equiv. 27.3 mL.) is added. The resulting mixture is stirred at the range between 17° C. and 35° C., and the solid precipitate is formed over 10 hours to 24 hours. Later, the mixture filtered and the cake is washed with a mixture of acetone and water (10 to 1) at 3 volumes or 33 mL. The cake is then dried under vacuum to a constant weight. The final weight is 8.34 g, 54.5% yield.
Reaction SMILES: [Br:1]Br.[N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[Br:1][CH2:14][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:3]=[CH:4][CH:5]=[CH:6]2)=[O:15]
Reactant: CC(=O)c1ccc2ncccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Bromine (6.69 g, 132 mmol) was added to a warm (100° C.) solution of 1-quinolin-6-yl-ethanone (Stage 1.4, 18.8 g, 110 mmol) in acetic acid (50 mL). The mixture was stirred at 100° C. for 45 min then cooled to rt. A precipitate was formed which was filtered off and washed with Et2O. Drying under HV at 50° C. afforded the title compound as a brown solid (tR 1.3 min (conditions 1), MH+=251.8).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([OH:6])[CH2:7][Cl:8]
Reactant: COC(=O)CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@@H](O)CCl

Procedure:
The procedure of example 369 was repeated using methyl-4-chloroacetoacetate as the substrate to afford methyl-4-chloro-3(R)-hydroxybutyrate, [α]D23 +21.15° (c, 4.2 CHCl3).