Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:5][C:4]2[CH:6]=[C:7]([F:20])[C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:27]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)cc(Nc2cc(F)c(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
162 mg (0.55 mmol) of 3,5-difluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 90 mg (0.55 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 6 ml of water/ethanol 1:1. 56 μl (0.65 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux for 3 h. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([OH:41])([C:39]#[CH:40])[CH3:38])[CH:32]=1>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: C#CC(C)(O)c1cccnc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC(C)(O)c3cccnc3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-3-yl)but-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(pyridin-3-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 9.05 (s, 1H), 8.86 (d, J=8 Hz, 1H), 8.80 (s, 1H), 8.08 (m, 1H), 7.80 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.49 (d, J=8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.87 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2. found: 528.1.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O.CN(C)C=O>C(Cl)Cl>[Cl:20][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nc(-c2ccccc2)nc2ccccc12
Temperature: 0 °C

Procedure:
To a mixture of 20.8 g of 2-phenylquinazolin-4(3H)-one and 195 ml of thionyl chloride was slowly added 6.85 g of dimethylformamide and the mixture was heated under reflux for 75 minutes. The mixture was poured into 1000 ml of ice and the ice allowed to melt. The precipitate was collected by filtration to give a tan solid, m.p. 135°. The still-moist solid was dissolved in methylene chloride, the solution was dried over magnesium sulfate and was filtered. The filtrate was evaporated to dryness and the residue recrystallized from hexane to give 10.45 g of 4-chloro-2-phenylquinazoline which melted at 127°-128.5°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12](=[O:20])[NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>ClCCl>[C:7]([O:11][C:12]([NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH:16]=[O:17])=[O:20])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CCO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
##STR105## Dimethylsufoxide (1.22 ml, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 ml, 12.9 mmol) at -78° C. in dichloromethane (15 ml). The mixture was stirred for 15 min at -78° C. A solution of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6 mmol) in dichloromethane (10 ml) was added dropwise over a period of 15 min. The solution was stirred at -78° C. for another 15 min. Triethylamine (6.0 ml, 43 mmol) was added. The solution was stirred at -78° C. for 5 min and then warmed to room temperature. The solution was diluted with dichloromethane (100 ml) and extracted with 1N hydrochloric acid (100 ml). The aqueous phase was extracted with dichloromethane (50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate/heptane (1:3) to give 1.10 g of 3-(tert-butoxycarbonylamino)-3-methylbutanal.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:7][C:6]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH:34]([C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=O>>[CH3:2][C:3]1[S:7][C:6](/[CH:8]=[CH:34]/[C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[N:5][C:4]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Agent: [Cl-]
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccccc3)c(C)s2)cc1

Procedure:
(5-Methyl-4-phenyl-2-thiazolylmethyl)triphenylphosphonium chloride and methyl 4-formylbenzoate were reacted in the same manner as in Reference Example 10 to yield methyl (E)-4-[2-(5-methyl-4-phenyl-2thiazolyl)vinyl]benzoate, which was then recrystallized from ethyl acetate to yield colorless plates having a melting point of 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].BrBr.[BrH:13].[Br-:14]>C(Cl)(Cl)(Cl)Cl>[Br:13][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[C:5]([Br:14])[C:6]=1[CH3:8]
Reactant: [Br-]
Reactant: Br
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(O)c(C)c(Br)c(C)c1Br

Procedure:
A 136.2 gram portion of 2,4,6-trimethyl phenol (1 mole) is dissolved in 2 liters of carbon tetrachloride. Using a water bath for cooling, 230 ml of bromine (4.5 moles) is added at 20° C. to 26° C. over a period of 15 minutes. Hydrogen bromide gas is given off during the bromide addition, and a slurry of 3,5-dibromo-2,4,6-trimethylphenol is obtained. The temperature is increased to 70° C. to 75° C., and in the process, a solution is obtained. The solution is held at that temperature for 2 hours. The unreacted bromine is removed by distillation with the aid of 1 liter of carbon tetrachloride. When 1 liter of solvent remains with the product, the solution is cooled to 25° C. The light brown solid obtained is filtered and dried under a vacuum for 5 hours. A yield of 260 g is obtained, which analyzes by gas chromatography as 99% tribromomesitol.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:2]=1.C(N(CC)CC)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[Cl:7][C:6]1[CH:1]=[CH:2][C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])=[C:4]([O:8][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of triclosan (7.53 grams, 26 mmol) and triethylamine (8.2 grams, 81 mmol) in acetone (50 mL) at 0° C. was added benzyloxy acetyl chloride (10 grams, 54.2 mmol) drop wise. The reaction mixture was stirred at room temperature for 18 hours. Solids were filtered off and poured onto cold water (100 mL). Crude 4 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×50 mL), and water (2×50 mL). The chloroform layer was dried over sodium sulphate and distilled off to get crude 4.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:25])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)C(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(COc1ccc2ccccc2c1)Nc1ccc(C(=O)C(=O)O)cc1
Yield: 90.6 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in hot methanol (10 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (2.5 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), faltered, and evaporated to give the crude product. Crystallization from acetone-hexane provided 0.61 g of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid as a colorless solid, mp 215°-216° C.
Reaction SMILES: Br[C:2]1(Br)[C:4]2([CH2:8][C@@H:7]([C:9]([OH:11])=[O:10])[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5]2)[CH2:3]1.OP=O.C(N(CC)CC)C>O.C(#N)C>[C:15]([O:14][C:12]([N:6]1[C@H:7]([C:9]([OH:11])=[O:10])[CH2:8][C:4]2([CH2:3][CH2:2]2)[CH2:5]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)O)CC2(Br)Br
Agent: O=PO
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1C(=O)O
Temperature: 100 °C
Yield: 69 %

Procedure:
To a mixture of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.7 g, 21.8 mmol), 50 wt % hypophosphorus acid (25.9 mL, 9 eq) and triethylamine (44.3 mL, 10 eq) in water (104 mL, 12 volumes) was added V-50 (591 mg, 0.1 eq) in 2 mL of 50% aqueous acetonitrile. The mixture was heated at 100° C. During the heating, additional 0.1 eq of V-50 was added to the reaction mixture every 30 minutes. Totally, 0.7 eq of V-50 was added. After heating at 100° C. for 4 hrs, the reaction mixture was evaporated and treated with 2N NaOH. It was extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2N HCl, extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (3.63 g, 69%) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 4.51-4.42 (m, 1H), 3.48-3.11 (m, 2H), 2.27-1.93 (m, 2H), 1.50/1.45 (two overlapping s, 9H), 0.71-0.59 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1I.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[S:28][C:25]1[S:26][CH:27]=[C:23]([C:16]2([OH:15])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:24]=1
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Reactant: CN1C(=O)CCc2cc(I)c(F)cc21
Product: CC1CC(O)(c2csc(Sc3cc4c(cc3F)N(C)C(=O)CC4)c2)CCO1
Yield: 85 %

Procedure:
Using an analogous procedure to that described in Example 5, 7-fluoro-6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give 4-[2-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]-4-hydroxy-2-methyltetrahydropyran in 85% yield as a gum;
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:10]1[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1c1ccccc1
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 90 °C

Procedure:
A deoxygenated mixture of crude tert-butyl(2S)-2-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylate (5-4, 7.65 mmol), 2,5-difluorophenyl boronic acid (1.81 g, 11.5 mmol), aqueous Na2CO3 solution (2 M, 11.5 mL, 23.0 mmol), and Pd(PPh3)4 (0.442 g, 0.383 mmol) in dioxane (100 mL) was heated at 90° C. for 45 minutes. The reaction mixture was cooled, then partitioned between brine (200 mL) and a 1:1 mixture of ethyl acetate and hexane (200 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2, 0-50% EtOAc/hexanes gradient) to provide tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5) as a white solid. LRMS m/z (M+H CH3) 358.0 found, 358.2 required.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=1
Reactant: COc1cnc(Cn2ccnc2-c2ncccn2)c(Cl)n1
Reactant: C1CCNCC1
Product: COc1cnc(Cn2ccnc2-c2ncccn2)c(N2CCCCC2)n1
Temperature: 110 °C

Procedure:
A mixture of 2-[1-(3-chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (30 mg, 0.099 mmol), and piperidine (1 mL) is heated at 110° C. in a sealed tube for 1 hour. On cooling, the volatile materials are removed in vacuo and the residue is purified by PTLC (silica gel; 10% MeOH in DCM) to give 35 mg of 2-[1-(5-Methoxy-3-piperidin-1-yl-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine. 1H NMR (CDCl3) 8.74 (d, 2H), 7.62 (s, 1H), 7.21 s, 1H), 7.08–7.15 (m, 2H), 5.86 (s, 2H), 3.87 (s, 3H), 3.06–3.15 (m, 4H), 1.52–1.66 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][Si:12](Br)([CH3:14])[CH3:13].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][Si:12]([CH3:14])([CH3:13])[NH:4][C:3]1[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[Cl:1]
Reactant: C[Si](C)(C)Br
Reactant: Cc1ccc(Cl)c(N)c1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)c(N[Si](C)(C)C)c1Cl
Yield: 73.6 %

Procedure:
A solution of 50 ml of benzene, 4.0 g (22.7 mmole) of 2,6-dichloro-3-methylaniline, 10.67 ml (80.8 mmole) of trimethylsilyl bromide, and 13.1 ml (94.0 mmole) of triethylamine was heated at reflux over 42 hours. The product was isolated as described in Example 1 to provide 4.14 g (16.7 mmole, 73.5 percent yield) of 98.0 percent pure N-trimethylsilyl-2,6-dichloro-3-methylaniline as a light yellow oil, b.p. 64°-68° C. at 0.03 mm.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[OH-].[NH4+:19]>>[ClH:17].[NH2:19][S:14]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][CH2:13][NH:4][CH2:5]2)=[CH:10][CH:9]=1)(=[O:16])=[O:15]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: [NH4+]
Agent: [OH-]
Product: Cl
Product: NS(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ammonium hydroxide (conc., 20 mL) was added to 2-acetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (2 g). The mixture was stirred at rt for 16 h. The ammonium hydroxide was evaporated under vacuum and hydrochloric acid (10%, 50 mL) was added to the residue. The mixture was heated at reflux for 4 h and the aqueous was evaporated under vacuum to afford 7-aminosulfonyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride (1.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10]C)=O)#[N:2].[C-]#N.[Na+].CO.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CS(C)=O>[CH:19]([NH:22][C:8](=[O:10])[C:7]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[OH:13])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: CC(C)N
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)NC(=O)c1cc(C#N)ccc1O
Temperature: 60 °C
Yield: 93 %

Procedure:
Methyl 5-cyano-2-hydroxybenzoate (8.85 g; 50 mmol; see Example 10(b) above) and NaCN (250 mg; 5 mmol) were dissolved in DMSO (10 mL) and MeOH (50 mL) and iso-propyl amine (25 mL) was added. The reaction mixture was heated (60° C. ) in a sealed steel vessel for 10 h, the MeOH was removed under reduced pressure and H2O (500 mL) was added. The solution was acidified with HCl (pH 1), filtered and the precipitate was washed with H2O giving the sub-title compound in a 93% yield.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:22][CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>CO.O1CCCC1>[CH3:1][O:20][C:19](=[O:21])[CH:18]([CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[NH:17][S:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=1)(=[O:15])=[O:16]
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(S(=O)(=O)NC(CCN2C(=O)c3ccccc3C2=O)C(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(CCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(OC)cc1
Yield: 96 %

Procedure:
After addition of trimethylsilyl chloride (0.65 g, 5.1 mmol) to a solution of (±)-N-(4-methoxybenzensulfonyl)-2-(2-phthalimidoethyl)glycine (1.08 g, 2.6 mmol), the product of Example 21, in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), the mixture was heated under reflux for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure. To the residue, a saturated aqueous solution of sodium hydrogencarbonate was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue for caking to afford the desired compound (yield 96%) as a white powder.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[NH:8][CH2:9][CH3:10])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[N:8]([CH2:9][CH3:10])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), 2,4-dinitro-N-ethylaniline (0.42 g (1.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.57 g (2.99 mmol)) was added. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (65%) of the title compound as pale yellow crystals.
Reaction SMILES: O[C:2]1(C2C=CC=CC=2OC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].Br[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1>CCOCC.C1COCC1>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH:2]2[C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:4]([C:11]3[CH:12]=[CH:13][C:14]4[O:17][CH2:18][O:19][C:15]=4[CH:16]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Reactant: COc1ccc(Br)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Ethyl (1RS) 1-Hydroxy-1-(methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate, A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10: 1 Et2O/ THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:13]=1)[CH2:9][C:10]#[CH:11]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:16][N:15]=2)=[CH:22][CH:21]=1
Reactant: C#CCCc1cc(-c2ccc(F)cc2)no1
Reactant: Brc1ccccn1
Product: Fc1ccc(-c2cc(CCC#Cc3ccccn3)on2)cc1
Yield: 25 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (40 mg, 0.26 mmol) and 5-but-3-ynyl-3-(4-fluoro-phenyl)-isoxazole (55 mg, 0.26 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to 7:3) to yield 19 mg (65 μmol, 25%) of 2-(4-(3-(4-fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine as a white solid (M.P.=83-84° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1ccccc1OCc1cccc(Cl)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCc3cccc(Cl)c3)n2)c1

Procedure:
Example 28 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {2-[(3-chlorobenzyl)oxy]phenyl}boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.