Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])(C)C)=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:7]([CH:9]=[C:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][CH2:31][CH2:2][CH3:5])=[O:26])[CH2:23][CH2:24]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.81 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in THF (26.3 mL) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (4.47 mL, 0.0276 mol) in THF (33.6 mL). The reaction was warmed to RT and then cooled at 0° C. again. To the reaction mixture was then added a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.0 g, 0.025 mol) in THF (6.72 mL). The reaction was allowed to warm up to RT and stirred overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The crude mixture was purified on silica gel eluting with EtOAc in hexanes (0-60%) to give the desired product (5.4 g, 96.81%). LCMS: (M+Na)=244.9, (M−56+H)=167.0.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24](OC)=[O:25]>>[NH2:8][C:9]1[CH:10]=[C:11]([S:15]([N:18]2[C:24](=[O:25])[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:29][CH:28]=3)[NH:30][C:31]2=[O:32])(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(S(N)(=O)=O)c1
Product: Nc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 49 %

Procedure:
From 3.5 g (12.9 mmol) of 3-t-butoxycarbonylaminobenzenesulfonamide and 3.9 g (12.8 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a similar manner to Preparation Example 7, 2.2 g (yield 49%: 4 steps) of the title compound was obtained. Property: colorless crystals, melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6): 5.72 (2H, s), 6.87 (1H, d), 7.12 (1H, s), 7.23-7.27 (2H, m), 7.33 (1H, s), 7.86 (1H, d), 11.61 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:12][C:3]=12.C(N(CC)CC)C.[NH2:28][CH2:29][C@@H:30]([OH:32])[CH3:31]>C1COCC1>[CH3:9][S:8][C:6]1[N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:12][C:3]2=[C:2]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])[N:7]=1
Reactant: CSc1nc(Cl)c2cnn(COCC[Si](C)(C)C)c2n1
Reactant: C[C@H](O)CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(NC[C@@H](C)O)c2cnn(COCC[Si](C)(C)C)c2n1
Reaction time: 4 h
Yield: 107.4 %

Procedure:
4-Chloro-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (391 mg, 1.182 mmol) was dissolved in 5 mL of dry THF. Triethylamine (239 mg, 2.363 mmol) was added, and the reaction mixture was stirred for four hours. (S)-1-Amino-propan-2-ol (93 mg, 1.241 mmol) was then added, and the reaction mixture was stirred for 64 hours. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure to give (R)-1-[6-Methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (469 mg). Mass Spec. M+H=370.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH:34](C#N)[CH2:33][NH:32][C:31]=4[CH:38]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.[CH3:44][O-:45].[Na+].[CH3:47][OH:48]>>[CH3:44][O:45][C:47]([CH:34]1[CH2:33][NH:32][C:31]2[CH:38]=[C:27]([CH2:26][C:21]3[CH:20]=[C:19]([C@H:8]4[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]4)[CH:24]=[CH:23][C:22]=3[Cl:25])[CH:28]=[CH:29][C:30]=2[O:35]1)=[O:48]
Reactant: CO
Reactant: C[O-]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCC(C#N)O4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Product: COC(=O)C1CNc2cc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (180 mg) in methanol (2 mL) was added sodium methoxide (20 mg). After stirring at room temperature overnight, the reaction mixture was concentrated to furnish 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid methyl ester. The resulting crude material was taken for the further conversion (195 mg).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH2:4][CH:5]=[CH2:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C=CCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and 3-(4-(3-butenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (583 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 890 mg (96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccccc3F)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3F)c2O1)OCc1ccccc1
Yield: 84 %

Procedure:
Treatment of (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.5 g, 5.36 mmol) with diisopropylethylamine (1.04 g, 8.04 mmol) and benzyl chloroformate (1.01 g, 5.89 mmol) generally according to the procedure described for Intermediate 12 afforded 1.7 g (84%) of (±)-benzyl[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil Rf=0.68 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C22H18FNO3: C, 72.72; H, 4.99; N, 3.85. Found: C, 72.65H, 5.41; N, 3.47. Chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=13.628 min, Chiralcel OJ, hexane:isopropanol 9:1); Fraction 2 (Rt=17.247 min, Chiralcel OJ, hexane:isopropanol 9:1).
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].BrN1[C:21](=O)[CH2:20][CH2:19]C1=O>O1CCCC1>[CH:13]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][C:7]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:20]([CH3:21])[CH3:19])[CH:1]([CH3:3])[CH3:2])=[CH:6]1)([CH3:15])[CH3:14]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)[Si](c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 137.4 %

Procedure:
The product from step (a) (102.6 g) was dissolved in tetrahydrofuran (600 ml) and treated with N-bromosuccinimide (89 g) at -78° C. under nitrogen for 15 minutes. The reaction was allowed to come to ambient temperature over one hour, concentrated, diluted with hexane, filtered and the solvent removed. The residue was dissolved in tetrahydrofuran (600 ml), cooled to -78° C., and tert-butyl lithium in pentane (588 ml 1.7M) was added. After one hour elemental sulfur (16 g) was added and the mixture was stirred for one hour at ambient temperature. The reaction was cooled to -78° C. and triisopropyl silyl chloride (98 g) was added and the reaction was allowed to warm to room temperature. After 24 hrs the solvent was removed under reduced pressure and the residue in diethyl ether was washed with water, dried over sodium sulfate, filtered, concentrated and distilled at 160°-205° C. (0.2 mm) to give a colorless viscous oil (119.8 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH2:17])[C:8]1=[O:19])(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH:17][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[C:22]([C:31]([F:32])([F:34])[F:33])[CH:23]=2)[C:8]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCn1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 45 °C
Reaction time: 96 h

Procedure:
A reaction vial was charged with 2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (60.0 mg, 0.000214 mol), 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (57.0 mg, 0.000256 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (203 mg, 0.000534 mol), N,N-diisopropylethylamine (0.093 mL, 0.00053 mol) and methylene chloride (3 mL, 0.05 mol), and the reaction mixture was stirred at 45° C. for 4 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford the product as a light yellow solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a solution of methyl 2-phenylsulfonylamino-5-chlorobenzoate (600 mg; prepared in Reference Example 2.) in the mixture of THF-MeOH (6 ml+3 ml), 2N NaOH solution (2 ml) was added. The mixture was stirred for 2 days. To the reaction mixture, 1N HCl (4.5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was washed and dried over to give the title compound (575 mg) having the following physical data.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].C(O)(=O)C>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of methyl 2-(5-formyl-2-thienyl)acetate (3.88 g, 21.1 mmol) in methanol (4 mL) and tetrahydrofuran (16 mL) was added sodium borohydride (399 mg, 10.5 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 1 h. Sodium borohydride (399 mg, 10.5 mmol) was added and the mixture left to stir at 0° C. for 2 h. Acetic acid (1.2 mL) was added and the reaction solution concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-30% ethyl acetate in iso-hexane to give the title compound as a yellow oil (1.1 g, 28%).
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:19])[CH:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])=[N+]=[N-].C(Cl)(Cl)[Cl:21].[H][H]>CO.[Pd]>[ClH:21].[NH2:1][CH2:4][CH:5]([OH:19])[CH:6]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CN=[N+]=[N-]
Reactant: [H][H]
Reactant: ClC(Cl)Cl
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CN
Product: Cl

Procedure:
The resultant compound of Example 75 (400 mg) dissolved in methanol containing added CHCl3 was hydrogenated over 10% Pd/C (40mg) with 3 atmospheres hydrogen. Filtration and evaporation gave the desired compound (305mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:18][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(CCl)cn1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2Cc2ccc(C)nc2)C1
Yield: 15.7 %

Procedure:
Preparation of the title compound was carried out according to General Method 4. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 ml) at 120° C. for 16 h to obtain 50 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (100-200 mesh or 230-400 mesh) using methanol-dichloromethane gradient
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[OH-].C([N+](C)(C)C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10]C=1.[C:18]([C-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)(=[O:21])[CH:19]=[CH2:20].[CH-]1C=CC=C1.[Fe+2:32]>C(O)C>[N+:1]([CH:4]([CH3:5])[CH2:20][CH2:19][C:18]([C-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)=[O:21])([O-:3])=[O:2].[CH-:10]1[CH:11]=[CH:12][CH:13]=[CH:8]1.[Fe+2:32]
Reactant: CC[N+](=O)[O-]
Reactant: C=CC(=O)[c-]1cccc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [Fe+2]
Agent: [OH-]
Agent: c1cc[cH-]c1
Solvent: CCO
Product: CC(CCC(=O)[c-]1cccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
Nitroethane (3g; 40 m mole) in ethanol (120 ml) was heated under reflux and under nitrogen for 10 minutes with benzyltrimethyl ammonium hydroxide (1 ml) and then cooled to room temperature. Acryloylferrocene (6.5g; 27.1 mole) was then added and the solution was stirred for 1 hour and then filtered. The filtrate was concentrated on the rotary evaporator, then poured into water and extracted with chloroform. The organic extract was washed (water) and dried (sodium sulphate) to give a brown solid which was recrystallised from cyclohexane/petroleum ether to give 4-nitropentanoyl ferrocene (1.65g; 19.2%) mp 79°-80°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](Cl)=[O:22].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH2:20][O:12][C:3]=2[CH:4]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 2 -amino-5 -methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (2.20 g) in dimethylformamide (30 ml) were added potassium carbonate (4.00 g) and 2-chloroacetyl chloride (1.50 g) and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.00 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[N:9][NH:8][C:7]=3[C:11]([NH2:13])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[N:9][NH:8][C:7]=3[C:11]#[N:13]
Reactant: CC1(C)C2Cc3c(n[nH]c3C(N)=O)C21
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C)C2Cc3c(n[nH]c3C#N)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide (0.532 g, 2.79 mmol) was taken up in THF (150 mL) and trifluoroacetic anhydride (0.936 g, 4.46 mmol) added. The resulting solution was stirred at room temperature under argon for 1 hour. Ethyl acetate (50 mL) was added and solvent removed under reduced pressure. The resulting pale yellow oil was taken up in DCM (100 mL), washed with saturated aqueous sodium bicarbonate solution (40 mL) and solvent removed under reduced pressure. The resulting white solid was taken up as a suspension in DCM (20 mL) and filtered to give (±)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile as an off-white solid. m/z (ES+): 174 [M+H]+
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.CO[Si:9]([CH3:12])([CH3:11])Cl.C1C[O:16][CH2:15]C1>C1(C)C=CC=CC=1>[CH3:15][O:16][C:3]1[CH:2]=[CH:6][CH2:5][C:4]=1[SiH:9]([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CO[Si](C)(C)Cl
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: Cc1ccccc1
Product: COC1=C([SiH](C)C)CC=C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
16.8 ml (0.22 moles) of a suspension of sodium in toluene at 30% are charged into a 250 ml flask. The mixture is diluted with 100 ml of THF and cooled to 0° C. 18.5 ml (0.22 moles) of cyclopentadiene diluted in 50 ml of THF are slowly added dropwise (about 60 minutes). The resulting solution is left under stirring at room temperature for a whole night, is then cooled to 0° C. and 29 ml (0.22 moles) of methoxydimethylchlorosilane fresh distillate (PETRARCH: 90%) are slowly added dropwise. The reaction is carried out at 0° C. for 3 hours. After filtration of the salt formed and evaporation of the solvent, a dark yellow oily liquid is obtained which, on distillation at 160°-162° C. gives 7.5 g of the desired product with a purity of 95.5% (GC), and a yield of 24%.
Reaction SMILES: O[CH:2]([CH:34]([CH3:36])[CH3:35])[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][C:21]([C:23]3[NH:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[O:22])[CH:14]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:35][CH:34]([CH3:36])/[CH:2]=[CH:3]/[S:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][C:21]([C:23]3[NH:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[O:22])[CH:14]=2)=[CH:11][CH:12]=1)(=[O:5])=[O:6]
Reactant: CC(C)C(O)CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)/C=C/S(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a suspension of N-([4′-[(2-hydroxy-3-methylbutyl)sulfonyl]biphenyl-3-yl]methyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 105 (0.300 g, 0.593 mmol) and triethylamine (0.579 mL, 4.15 mmol) in THF (6 mL) was added dropwise methanesulfonyl chloride (0.083 mL, 1.07 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound as a pale-yellow powder (0.220 g, 76%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)C.[OH-].[Na+].O>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:5]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (47 mg, 0.125 mmol) in ethanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (90 μL) and the mixture is stirred at 60° C. for 20 h. Another portion of (S)-3-chloro-propane-1,2-diol (60 μL) is added and stirring is continued at 60° C. for 5 days. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-propan-1-one (6 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.25; 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.30-7.21 (m, 4H), 6.88 (s, 2H), 4.11-4.05 (m, 1H), 3.87-3.80 (m, 4H), 3.18-3.11 (m, 2H), 2.98-2.85 (m, 4H), 2.39 (s, 3H), 2.25 (s, 6H), 1.29 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]([C:12]1[CH:13]=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([OH:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:11])[CH2:2][CH2:3][CH3:4].Cl[S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[C:41]([OH:48])[CH:40]=1)(=[O:38])=[O:37]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][S:36]([C:39]2[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[C:41]([OH:48])[CH:40]=2)(=[O:38])=[O:37])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Yield: 40.6 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 2, using (2-n-butyl-benzofuran-3-yl)-(2′-hydroxy-[1,1′;3 ′,1″]terphenyl-5′-yl)-methanone (0.136 g, 0.305 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.144 g, 6.09 mmol) to give 0.080 g (38%) of the title compound as a white solid, mp 190-197° C.; 1H NMR (DMSO-d6) δ0.77 (t, 3 H), 1.22 (sextet, 2 H), 1.63 (quintet, 2 H), 2.83 (t, 2 H), 6.55 (d, 1 H), 6.66 (dd, 1 H), 7.28-7.38 (m, 8 H), 7.41-7.43 (m, 4 H), 7.51 (dd, 1 H), 7.57 (d, 1 H), 7.64 (d, 1 H), 7.74 (s, 2 H). IR (KBr) 2900, 1675, 1390 and 1190 cm−1. mass spectrum (−ESI), mlz 645 (M−H). Anal. Calcd. for C38H30O8S.2H2O: C, 66.85; H, 5.02; N, 0.00. Found: C, 66.80; H, 4.88; N.0.07.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([OH:12])=[O:11])[N:3]=1.I[CH3:14]>>[CH3:14][O:11][C:10]([C:4]1[N:3]=[C:2]([I:1])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(C(=O)O)nc1I
Product: COC(=O)c1ccc(OC)c(I)n1

Procedure:
Under the conditions of example 1 D, 9.8 g of 2-iodo-3-methoxy-pyridine-6-carboxylic acid is reacted with 2.5 ml of iodomethane and worked up. 7.4 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester of melting point 175°-178° C. is obtained.