Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[I:16]I.C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>C(#N)C>[I:16][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCc1cccc(OC)c1
Reactant: II
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OC)ccc1I
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of ester 25 (1.618 g, 7.77 mmol) in acetonitrile (100 mL), iodine (1.972 g, 7.77 mmol) and n-butyltriphenylphosphonium peroxodisulfate (6.455 g, 7.77 mmol) were added and refluxed for 45 min. The reaction mixture was cooled to room temperature and the excess of iodine was removed by dropwise addition of 1M Na2S2O3 solution. The colourless solution was transferred to a separatory funnel and the organic layer was separated and dried over Na2SO4. Evaporation of the solvent followed by means of column chromatography on silica gel (hexane/isopropylether 10:1) gave 1.982 mg of iodinated ester 26 as a yellowish oil. Yield 76%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.65 (d, J=8.7 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 6.51 (dd, J1=8.7 Hz, J2=3.0 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.00 (t, J=7.9 Hz, 2H), 2.60 (t, J=7.9 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 172.4, 160.0, 144.0, 139.9, 115.5, 114.1, 88.6, 60.5, 55.3, 35.9, 34.4, 14.2; HRMS (EI) m/z: calcd for C12H15|O3: 334.0065. found: 334.0082.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]O)[CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:43])([F:42])[C:35]1[C:39]([CH2:40][OH:41])=[CH:38][NH:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[OH:41][CH2:40][C:39]1[C:35]([C:34]([F:43])([F:42])[F:33])=[N:36][N:37]([CH2:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C@@H:11]([NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]3)[CH:38]=1
Reactant: OCc1c[nH]nc1C(F)(F)F
Reactant: O=C(N[C@@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)OCc1ccccc1
Temperature: 60 °C
Yield: 76.9 %

Procedure:
(R)-benzyl-5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (5.08 mmol, 1.51 g) was dissolved in DCM (20 mL), thionyl chloride (10.16 mmol, 0.741 mL, 1.208 g) added and the resultant solution stirred at room temperature for 45 min. The sample was concentrated and azeotroped with DCM (×4). Potassium carbonate (15.23 mmol, 2.105 g) was added followed by DMF (20 mL) and (3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (5.08 mmol, 0.843 g) and the mixture heated to 60° C. for 1 h. The mixture was concentrated and partitioned between EtOAc/water. The aqueous layer was twice extracted with EtOAc and combined organics dried, filtered and concentrated to give a yellow oil which was purified on silica eluting with 0.5% MeOH/DCM to give (R)-benzyl 5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate as a light coloured oil (1.74 g, 77%). 1H NMR (400 MHz, CDCl3) δ 1.83 (t, 1H) 2.79 (m, 2H) 3.27 (m, 2H) 4.52 (bs, 1H) 4.64 (d, 2H) 4.99 (bs, 1H) 5.09 (bs, 2H) 5.25 (s, 2H) 7.05-7.11 (m, 2H) 7.19 (m, 1H) 7.26-7.40 (m, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([NH:6][CH3:7])=[O:5])[CH3:2].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([N:6]([CH3:7])[C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18])=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)NC
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 79 %

Procedure:
In 300 ml of anhydrous dichloromethane, 13.0 g (0.1 mole) of 1,1-diethyl-3-methylurea and 12.0 g (0.1 mole) of phenylisocyanate were dissolved. Under cooling the mixture with stirring, 26.0 g (0.1 mole) of stannic chloride was added dropwise. The reaction was continued at a room temperature for 15 hours and the reaction mixture was treated by a procedure similar to that of mentioned in Example 1, and recrystallized from ethanol-petroleum ether to obtain 19.7 g (yield 79%) of 1,1-diethyl-3-methyl-5-phenylbiuret having a melting point of 88°-89.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([C:20]4[N:21]=[N:22][NH:23][N:24]=4)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH2:25])=[CH:4][CH2:3]1.[K+].[C:28]([C:30]1[N:31]=[C:32]([C:43]([O-])=[O:44])[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=1)#[N:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([C:20]4[N:21]=[N:22][NH:23][N:24]=4)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:43]([C:32]2[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=[C:30]([C:28]#[N:29])[N:31]=2)=[O:44])=[CH:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3(c4nn[nH]n4)CCOCC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(C3(c4nn[nH]n4)CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
To the crude product of 2-(4,4-dimethyl-cyclohex-1-enyl)-4-[4-(2H-tetrazol-5-yl)-tetrahydro-pyran-4-yl]-phenylamine (76 mg, ca. 0.22 mmol) in 2.5 mL of DMF was added potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 72 mg, 0.24 mmol), PyBroP (110 mg, 0.236 mmol) and DIEA (112 μL, 0.645 mmol). After stirring at RT for 2 d, the mixture was treated with 20 mL of H2O and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (2×10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (1-3 MeOH/DCM) to afford the title compound (55 mg, 42% for 2 steps) as a faint brown solid. Mass spectrum (ESI, m/z): Calcd. for C31H42N8O3Si, 603.3 (M+H). found 602.9.
Reaction SMILES: C[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.[CH:11](NC(C)C)(C)C.[Li]CCCC.Cl([O-])(=O)(=O)=O.[CH2:28]1[C:35]2[CH2:34][CH2:33][CH2:32][N+:31]=2[CH2:30][CH2:29]1.Cl>C1COCC1>[CH2:28]1[C:35]2([CH:9]3[S:10][C:5]4[C:6]([N:7]([CH3:11])[CH:2]=[CH:3][CH:4]=4)=[CH:8]3)[N:31]([CH2:32][CH2:33][CH2:34]2)[CH2:30][CH2:29]1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Cc1ccc2sccc2n1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CN1C=CC=C2SC(C34CCCN3CCC4)C=C21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
5-Methylthieno[3,2-b]pyridine (285 mg, 1.91 mmol, prepared according to Gronowitz et al., Acta Chemica Scandinavica B, 29:233-238 (1975)), diisopropylamine (270 uL, 1.91 mmol) and nBuLi (2.5 M in hexanes, 765 uL, 1.91 mmol) were combined in THF (8 mL). After 20 minutes of stirring, 1,2,3,5,6,7-hexahydro-pyrrolizinium perchlorate from Example 15a (200 mg, 0.95 mmol) was added. The mixture was allowed to warm to ambient temperature and 2 N aqueous HCl was added. The reaction mixture was washed with Et2O and the aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (3×). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford a solid (79 mg, 32%): 1H NMR (CDCl3, 300 MHz) δ 1.80-1.94 (m, 4H), 1.98-2.07 (m, 2H), 2.16-2.24 (m, 2H), 2.64 (s, 3H), 2.64-2.71 (m, 2H), 3.22-3.28 (m, 2H), 7.02 (d, J=8 Hz, 1H), 7.16 (s, 1H), 7.92 (d, J=8 Hz, 1H); MS (CI/NH3) m/z: 259 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH2:16])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18].[C:22](OC(=O)C)(=[O:24])[CH3:23].[C:29](OCC)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1>[C:22]([O:1][CH:2]([CH2:20][O:21][C:29](=[O:31])[CH3:30])[CH2:3][NH:4][C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH2:16])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18])(=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 g (0.475 mol) of 5-amino-2,4,6-triiodoisophthalic acid mono-(2,3-dihydroxy-propyl) amide is suspended in 1.4 liter of ethyl acetate, mixed with 178.07 g (1.74 mol) of acetic anhydride and 5.7 g (47.5 mmol) of 4-dimethylaminopyridine and the mixture is heated to boiling. The suspension changes into a solution from which the product quickly crystallizes out in the boiling heat. The acetylation is completed after 1 hour. The excess acetic anhydride is reacted to ethyl acetate by addition of ethanol, cooled to room temperature, the crystallizate is suctioned off, washed with ethyl acetate and dried in a vacuum at 50° C. The yield is 300.2 g (0.42 mol)=88.4% of theory.
Reaction SMILES: [C:1](=[N:34]O)([C:8]1[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[N:30]O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:30][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:1]([NH2:34])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:33][CH:32]=2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ON=C(c1ccccc1)c1ccc(OCCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(OCCCOc2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The dioxime from Step 2 (20 g) is dissolved in ethyl alcohol saturated with ammonia gas (220 ml) and Raney nickel W-6 (2 g) added. The mixture is subjected to 500 psi hydrogen pressure and heated at 90° for four hours. The catalyst is removed by filtration and the solvent is removed by distillation to yield 15.5 g (83% of theory) of pale yellow crystals mp 118°-9°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(OC(C)(C)C)=O.O.Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:21]([O:20][C:18]([O:17][C:10]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=Cc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
Poly (p-hydroxystyrene) (VP-8000, manufactured by Nippon Soda Co., Ltd., weight average molecular weight: 11,000) was dissolved in 40 ml of pyridine, and 1.28 g of di-t-butyl dicarbonate was added to the solution with stirring at room temperature. After performing the reaction at room temperature for 3 hours, the reaction solution was poured into 1 liter of ion exchange water containing 20 g of concentrated hydrochloric acid. The powder precipitated was filtered, washed with water, and dried, thereby p-hydroxystyrene/p-(t-butyloxycarbonyloxy)styrene copolymer (60/40) was obtained.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][N:10]([CH3:23])[C:11]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[C:14]=1[OH:22])=[O:12].N1C=CN=C1>C(Cl)Cl>[CH3:9][N:10]([CH3:23])[C:11]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[C:14]=1[O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:12]
Reactant: CN(C)C(=O)c1ccc2c(c1O)OCO2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1O[Si](C)(C)C(C)(C)C)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
t-Butyldimethylsilyl chloride (4.02 g, 26.67 mmol) in CH2Cl2 (25 ml) was added to a solution of N,N-dimethyl-4-hydroxy-1,3-benzodioxole-5-carboxamide (5) (4.49 g, 20.5 mmol) and imidazole (3.63 g, 53.3 mmol) in CH2Cl2 (25 ml). The solution was stirred for 3 h at rt, during which time a white solid precipitated. The mixture was washed with brine, dried over MgSO4 and concentrated. Chromatography on silica (hexane/ethyl acetate, 1:1) afforded 9 (5.44 g, 82%) as a crystalline solid. 1H NMR (270 MHz, CDCl3) ε 6.75 (d, J=8.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 5.92 (s, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 0.94 (s, 9H), 0.16 (bs, 6H). 13C NMR (100 MHz, CDCl3) ε 168.9 (C), 149.3 (C), 137.0 (C), 135.5 (C), 124.9 (C), 121.4 (CH), 102.8 (CH), 101.0 (CH2), 38.2 (CH3), 34.9 (CH3), 25.4 (3CH3), 18.1 (C), -4.6 (2CH3).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3cccc(F)c3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccc(F)c2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 7.5 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.68 g of methyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2,3-difluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetate in 6 cm3 of a water/methanol (30/70 by volume) mixture and 0.08 g of potassium hydroxide. The crude product (0.45 g) is dissolved in 7.5 cm3 of 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 10 cm3 of diethyl ether, brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution, then extracted with 2 times 20 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The product obtained is purified by chromatography on silica [eluent:methylene chloride/methanol (80/20 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.05 g of (2R,4R)-3-{3-{2-[4-tert-Butoxycarbonyl-2-(2,3-difluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetic acid is thus obtained in the form of an amorphous product.
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[C:21]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[CH:25][C:20]=3[O:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].[OH-].[K+]>C1COCC1.C(O)C.O>[CH2:27]([O:26][C:24]1[CH:23]=[CH:22][C:21]2[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]4)=[CH:18][O:19][C:20]=2[CH:25]=1)[CH3:28]
Reactant: CCOC(=O)c1cc2c(OCc3coc4cc(OCC)ccc34)cccc2n1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
4-(6-Ethoxy-benzofuran-3-ylmethoxy)-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (29a) (7.5 g, 15.6 mmol) is dissolved in 150 ml of a 1:1:1 mixture of THF, ethanol and water. And after addition of KOH pellets (4.4 g, 78.2 mmol) the mixture is stirred for 2 h (TLC control) at 85° C. Then the organic solvent is removed under reduced pressure. The residue is cooled to 0° C. and treated with 2M HCl. The crude product is filtered off and dried under high vacuum. The crude product is recrystallized from ethyl acetate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].B(F)(F)F.CCOCC>C(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: O=Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3-propane dithiol in CH2Cl2 (150 mL) at room temperature was dropwise added BF3.Et2O (6.3 mL, 50 mmol) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with CH2Cl2, filtered and the filtrate washed with brine, saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford a white solid, which was recrystallized from a 1:1 mixture of ether and hexane to afford 17.0 g (87%) of the title compound (21) as white crystalline needles. 1H NMR (CDCl3, 400 MHz): δ 1.91 (m, 1H), 2.14 (m, 1H), 2.89 (m, 2H), 3.04 (m, 2H), 5.16 (s, 1H), 7.35-7.28 (m, 3H), 7.46 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6]/[C:7](/[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[N:23]=1)=[N:8]/[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].[NH4+].[Cl-]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O.C(OCC)(=O)C>[NH2:8][C:7]([NH2:21])=[NH:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6](/[C:7](/[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[N:23]=1)=[N:8]/[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=1)[C:33](=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(/N=C(/NCc1ccc(F)c(Cl)c1)Nc1cccc(O)n1)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(Cc1ccc(F)c(Cl)c1)/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cccc(O)n1
Product: N=C(N)N
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
Pyridonyl guanidine compound (Z)-N-(((3-chloro-4-fluorobenzyl)amino)((6-hydroxypyridin-2-yl)amino)methylene)-4-(trifluoromethyl)benzamide was prepared based on the procedures described in Example 1. Then, (Z)-N-(((3-chloro-4-fluorobenzyl)amino)((6-hydroxypyridin-2-yl)amino)methylene)-4-(trifluoromethyl)benzamide (0.1 g, 0.214 mmol) was dissolved in pyridine (1 mL) with 4-dimethylaminopyridine (0.026 g, 0.214 mmol) under nitrogen at room temperature and acetic anhydride was added (0.022 g, 0.214 mmol). The reaction mixture was stirred at room temperature for 4 h forming a thick white slurry. Analysis by RP-HPLC indicated a ˜1:1 mixture of starting material and product. Additional pyridine (approximately 0.5 mL) and acetic anhydride (˜10 uL) were added. Stirring was continued for another 4 h then the mixture was diluted with water and ethyl acetate. Saturated aqueous NH4Cl was added to the mixture and the layers were separated. The organic layer was washed with water then brine and dried (MgSO4). Chromatography, eluting with 30-50% ethyl acetate in hexanes, gave a white solid which was triturated with diethyl ether to provide (E)-N-((N-(3-chloro-4-fluorobenzyl)acetamido)((6-hydroxypyridin-2-yl)amino)methylene)-4-(trifluoromethyl)benzamide (52 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[C:20]([Mg]Br)#[C:21][CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:18][CH2:19]1)([C:20]#[C:21][CH3:22])[OH:16]
Reactant: CC#C[Mg]Br
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Product: CC#CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1

Procedure:
1 -(4-Amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol was prepared from (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone and propynylmagnesium bromide according to Example 41.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][OH:16].C(N(CC)CC)C.[I-:26].[Na+]>ClCCl.CC(C)=O>[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][O:16][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][I:26])[CH:4]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: C[Si](C)(C)CCO
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)c1cccc(CI)c1
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a solution of 3-(chloromethyl)benzoyl chloride (2.5 g, 17.5 mmol) in dichloromethane (100 ml) was added 2-(trimethylsilyl)ethanol (1.72 ml, 12.0 mmol). Triethylamine, (9.21 ml, 66 mmol) was added and the reaction stirred overnight. The dichloromethane was evaporated and the crude material taken up in ether and washed with water. The ether layer was dried (sodium sulfate) and evaporated to give a slightly yellow mobile oil. The oil (2.7 g) was dissolved in acetone (30 ml) containing sodium iodide (1.5 g) and stirred for two hours. The solvent was removed and to the residue was added diethyl ether and the resulting mixture was filtered. The filtrate was evaporated to give a brown oil (3.68 g, 77%): 1H NMR (CDCl3) δ: 7.95, (1H, s), 7.85, (1H, d), 7.28, (1H, d), 7.17, (1H, t), 4.38, (2H, s), 4.33 (2H, m), 1.11 (2H, m), 0.00 (9H, s) ppm. Mass spectrum (M-I) 235.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:19][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 148.2 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 20.4 g (0.2 mol, 2.0 eq.) of 1-hexanol were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8 mL). Subsequently, the resultant was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 33.1 g of 4-hexyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:15].Cl.N1[CH:22]=[CH:21]C=CC=1>C(OC(=O)C)(=O)C>[C:21]([O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)(=[O:15])[CH3:22]
Reactant: O
Reactant: c1ccncc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(Oc2ccccc2)cc1

Procedure:
4-Phenoxyphenol (25.0 g, 134 mmol) is taken up in a mixture of pyridine (51 mL) and acetic anhydride (58 mL) and heated at reflux for 2 hours. The mixture is cooled and poured into 300 mL of water. The solution is made acidic with 2N hydrochloric acid and extracted three times with ether. The organic phase is washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. Purification of the residue by silica-gel flash chromatography (4:1 hexane/ethyl acetate) gives 4-phenoxyphenyl acetate as a colorless solid.