Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=NCC.C(NC(C)C)(C)C.Cl.[C:20]1([C:26]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])([OH:35])[CH:28]([OH:44])[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]([CH2:60][C:61](O)=[O:62])=[CH:52]1.Cl.[Cl-].[Na+]>C(Cl)Cl.O.ON1C2C=CC=CC=2N=N1>[C:45]1([C:26]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:34]3[CH:30]([CH2:31][N:32]([C:61](=[O:62])[CH2:60][C:53]4[C:54]5[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=5)[NH:51][CH:52]=4)[CH2:33]3)[C:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])([OH:35])[CH:28]([OH:44])[CH2:27]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 0 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
0.46 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.34 cm3 of diisopropylamine are added to a solution of 0.9 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5-diol hydrochloride, 0.4 g of 3-indolylacetic acid and 20 mg of 1-hydroxybenzotriazole hydrate in 90 cm3 of methylene chloride, cooled to 0° C. The mixture is stirred at room temperature for 15 hours, acidified with 0.1N HCl and then taken up in an aqueous saturated solution of sodium chloride. The organic phase is decanted, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The foam obtained is recrystallised in 10 cm3 of boiling acetonitrile. 0.85 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-perhydroisoindole-4,5-diol is obtained in the form of a white solid which melts at 266° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N12CCN(CC1)CC2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>CN(C)C=O>[CH3:21][N:22]([CH3:26])[C:23]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[S:24]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(C)cc1O
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1OC(=S)N(C)C
Temperature: 60 °C
Yield: 82.3 %

Procedure:
To a solution of methyl 2-hydroxy-4-methylbenzoate (109 g, 657.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (147.4 g, 1314.4 mmol) in N,N-dimethylformamide (300 mL) was added a solution of N,N-dimethylcarbamothioyl chloride (97.5 g, 788.6 mmol) in N,N-dimethylformamide (100 mL) at room temperature. After being heated at 60° C. for 4 hours, the mixture was cooled and poured onto ice. The formed precipitate was collected by filtration, washed with water (300 mL×3) and dried in vacuo to afford 137 g of methyl 2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate as an off-white solid (yield was 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:18](=O)N)(C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(=O)OI(C1C=CC=CC=1)OC(C(F)(F)F)=O.O.C(#[N:45])C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:45])([CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: CC1(C(N)=O)CCCN(C(=O)OCc2ccccc2)C1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: CC1(N)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
3-Carbamoyl-3-methyl-piperidine-1-carboxylic acid benzyl ester (500 mg, 1.81 mmol) in acetonitrile (10 mL) was treated with [bis(trifluoroacetoxyl)iodo]benzene (PIFA) (800 mg, 1.86 mmol) and water (2 mL), the mixture was allowed to stir at 25° C. for 3 hours. LCMS showed starting material consumed, the mixture was heated to 70° C. for 30 min to decompose excess PIFA. The mixture was purified by column chromatography (eluting with 30˜50% methanol in dichloromethane) to give 420 mg (93%) of 3-Amino-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method K, ESI): RT=0.95 min, m+H=249.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br.BrC1C=CC(NC(C2(C([O-])=O)CC2)=O)=C(C)C=1>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:26][CH2:25]2)=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: Cc1cc(Br)ccc1NC(=O)C1(C(=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
Into a 500 milliliter three-necked round-bottom reaction flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and outlet and oil bath was added 30.0 grams (0.10 mol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared as in Example A, 34.5 grams (0.25 mol) of anhydrous potassium carbonate, 100 milliliters of anhydrous dimethylformamide and 8.6 milliliters (0.10 mol) of 1,2-dibromoethane. The resulting mixture as stirred under a nitrogen atmosphere at a temperature of 65° C. for a period of 3 hours and then at a temperature of 80° C. for a period of 3.5 hours. Following this period, high pressure liquid chromatographic analysis showed the reaction to be incomplete. An additional 13.8 grams (0.10 mol) of anhydrous potassium carbonate was added and the reaction mixture was stirred at ambient temperature for a period of 16 hours. An additional 1.7 milliliters (0.02 mol) of 1,2-dibromoethane was then added and the reaction mixture was heated at a temperature of 75° C. for a period of 3.5 hours. Anhydrous potassium carbonate (6.0 grams, 0.043 mol) was then added and heating was continued for an additional 2.5 hours. The reaction mixture was then cooled, diluted with methylene chloride and filtered to remove suspended solids. Concentration under reduced pressure gave a brown liquid which was chromatographed on silica gel using 3:1 volume/volume hexane-ethyl acetate as the eluent. Early fractions contained 17.8 grams (55.0 mmol) of 1-(4-bromo-2-methylphenylaminocabonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 87.0° C.-90.0° C. The total yield was 56.0 percent based on a 96.7 weight percent assay of the starting ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccccc1CCl
Solvent: CCO
Product: COc1ccccc1CN1CCN(CCO)CC1
Yield: 80 %

Procedure:
2-Methoxybenzyl chloride (16 g) and 1-(2-hydroxyethyl)piperazine (13 g) in ethanol (50 ml) were heated under reflux for 4 hours. The solvent was removed under vacuum and the resulting oil was passed through a pad of silica gel eluting with 10% methanol-ammonia in dichloromethane to give 1-(2-hydroxyethyl)-4-[(2-methoxyphenyl)methyl]piperazine as a colourless oil (80%), 13C nmr (CDCl3) 157.4, 130.3, 127.8, 125.2, 119.8, 110.0, 59.5, 57.6, 55.2, 54.8, 52.7 and 52.4 ppm. This material (15 g) was treated at 0° C. with thionyl chloride (15 ml). The mixture was then heated at reflux for 2 hours. Toluene was added and the mixture was evaporated under reduced pressure. The resulting solid was collected and washed thoroughly to give the dihydrochloride of the title compound as a white solid, m.p. 276°-279° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccc(O)cc1
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: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(O)cc2)cc1
Yield: 24.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.017 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]([CH:25]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][N:26]2C(OCC2C=CC=CC=2)=O)=[CH:18]3)=[N:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]([CH:25]2[NH:26][CH2:27][CH2:28][N:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]2)=[CH:18]3)=[N:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:8]=1)[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2c(c1)cc(C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1)n2C
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2c(c1)cc(C1CN(C(=O)OC(C)(C)C)CCN1)n2C

Procedure:
Solution of 1-benzyl 4-tert-butyl 2-(5-(3-ethyl-6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-indol-2-yl)piperazine-1,4-dicarboxylate (71.4 mg, 0.11 mmol), prepared according to procedure described in Example 67, Step 3, in MeOH (1 mL) was hydrogenated over Pd/C (10% Degussa type, 10 mg) with H2-balloon. After 1 h complete consumption of starting material was observed. Catalyst was filtered and washed with MeOH (5 mL). Concentration of mother liquor afforded tert-butyl 3-(5-(3-ethyl-6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-indol-2-yl)piperazine-1-carboxylate which was used directly in the next step. LC-MS 509.3 [M+H]+, RT 1.28 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)([CH3:3])[CH3:2].O[C@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17]1.Cl.C(OC1C(O[C@@H]2CCC[C@H](N)C2)=CC=C2C=1C=NN2)CC.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[C:13]([O:14][C@@H:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH2:22])[CH2:17]2)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1c(O)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](O)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: CCCOc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, the 4-isopropoxy-1H-indazol-5-ol (118 mg, 0.614 mmol) obtained in Example 638 and the trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (100 mg, 0.408 mmol) obtained in Example 385, (b) were added to a solution of 90%-cyanomethylenetri-n-butylphosphorane (155 mg, 0.614 mmol) in toluene (4 ml) at room temperature, and the resulting mixture was heated to 100° C. After 4.5 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. The aqueous layer was re-extracted with chloroform and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). To the resulting oil was added a 30%-methylamine-ethanol solution at room temperature, and the resulting mixture was refluxed. After 4 hours, the mixture was concentrated under reduced pressure at room temperature, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain cis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine (71.0 mg, 60%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11](=[O:30])[NH:12][C:13]1([C:16](=[O:29])[NH:17][C:18]2([C:21]3[CH:26]=[C:25]([CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19]2)[CH2:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35]Br.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.CC#N.O>[CH2:3]([O:10][C:11](=[O:30])[NH:12][C:13]1([C:16](=[O:29])[NH:17][C:18]2([C:21]3[CH:26]=[C:25]([CH2:27][N:28]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:14][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccnc(C2(NC(=O)C3(NC(=O)OCc4ccccc4)CC3)CC2)c1
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NC1(C(=O)NC2(c3cc(CN4CCCC4)ccn3)CC2)CC1)OCc1ccccc1
Temperature: 80 °C
Yield: 35 %

Procedure:
{1-[1-(4-Aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid benzyl ester dihydrochloride (200 mg, 0.441 mmol) was dissolved in dry DMA (5 mL). 1,4-Dibromobutane (0.264 mL, 2.206 mmol) was added followed by Na2CO3 (0.234 g, 2.206 mmol). The reaction mixture was heated at 80° C. in a microwave reactor for 20 min. The reaction mixture was diluted with MeCN (4 mL) and water (1 mL) and filtered. The resultant crude product was purified by mass triggered LCMS using 5-35% MeCN/water as the gradient to afford 67 mg of {1-[1-(4-Pyrrolidin-1-ylmethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid benzyl ester.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1ccccc1C(F)(F)F
Yield: 42.1 %

Procedure:
Using the procedure of Step A of Example 6, 32.22 g of o-trifluoromethyl aniline and 26.52 g of valeryl chloride were reacted to form 20.63 g of N-(2-trifluoromethylphenyl)-pentanamide melting at 63° C which was used as is for the next step.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:13][CH:12]=2)[S:6]1(=[O:37])=[O:36])(C)(C)C>FC(F)(F)C(O)=O>[O:37]=[S:6]1(=[O:36])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])=[CH:13][CH:12]=2)[CH2:8][C:9](=[O:10])[NH:5]1
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CCNS(=O)(=O)c3ccc(Oc4ccccc4)cc3)cc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccc(CCNS(=O)(=O)c3ccc(Oc4ccccc4)cc3)cc2)S(=O)(=O)N1
Temperature: 170 °C
Reaction time: 0.01 h
Yield: 89.4 %

Procedure:
N-2-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]ethyl-4-phenoxy-benzenesulfonamide (10.0 mg, 0.0184 mmol) was dissolved in trifluoroacetic acid (2 mL). The reaction was heated to 170° C. in the microwave and held at that temperature for 45 seconds. The reaction was chromatographed on a 21.2 mm Luna C18 column using a 20–80% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 25 mL per minute over a 20 minute period. The major fraction was lyophilized to give a white powder (8 mg, 90%). 1H NMR (500 MHz, CD3OD): δ 7.76 (d, J=9.2 Hz, 2H), 7.42 (t, J=7.8 Hz, 2H), 7.37 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 7.21 (m, 1H), 7.07 (d, J=7.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.94 (m, 1H), 4.39 (m, 1H), 3.35 (m, 2H), 3.24 (m, 2H), 2.85 (m, 2H); LCMS found for C23H22N2O6S2 (M+H)+: m/z 487.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)[C:19](F)=[N:20][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH2:30][C:25]1[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([C:18]2[C:19]([NH:1][C:2]3[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=3)=[N:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)[N:24]=1
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Reactant: COc1ncc(N)cc1NS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ncc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
To a stirred solution of N-(5-amino-2-methoxypyridin-3-yl)methanesulfonamide (Step 4, 0.028 g, 0.13 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Step 1, 0.0364 g, 0.152 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 0.52 mL, 0.52 mmol) was added dropwise at 0° C. The solution was stirred at 0° C. for 1.5 h. The reaction mixture was poured into sat'd NH4Cl (15 mL) and stirred. The resulting solid was collected via filtration. The crude product was purified by preparative HPLC (column: Phenomenex, Gemni 5 micron C18 100×30 mm, 10%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The corresponding fractions were combined and concentrated. Sat'd NaHCO3 was added to the residue and sonicated. The resulting yellow solid was collected and washed with water and with MeOH to afford 5 N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)-2-methoxypyridin-3-yl)methanesulfonamide (12.9 mg, 23% yield) as bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1H) 9.27 (s, 1H) 8.72 (d, J=2.54 Hz, 1H) 8.32 (dd, J=10.47, 2.45 Hz, 2H) 8.09 (d, J=2.15 Hz, 1H) 7.77-8.01 (m, 2H) 3.91 (s, 3H) 3.05 (s, 3H) 2.44 (s, 3H). m/z (ESI, positive ion): 436.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:15][S:16]([O:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OS(C)(=O)=O
Temperature: 50 °C

Procedure:
Methyl 2-hydroxy-4-nitrobenzoate (19.7 g) was dissolved in 100 ml of chloroform and triethylamine (15 ml). The solution was kept at a temperature below 15° C., and methanesulfonylchloride (8.6 ml) was added dropwise. The solution was maintained at 50° C. for 1 hr, whereupon it was poured onto ice-hydrochloric acid and extracted with a total of 600 ml chloroform. The solution was dried with magnesium sulfate, treated with active carbon and evaporated. The product was recrystallized from methanol. Yield: 20 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.Br[CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2>O1CCCC1>[CH3:10][O:9][C:6]1[C@H:7]([CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[N:8]=[C:3]([O:2][CH3:1])[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=1
Reactant: BrCc1ccc2ncccc2c1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
To a cooled solution (−70° C.) of (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (25.8 g, 140 mmol, 2 eq.) in tetrahydrofuran (200 mL) was added dropwise n-butyllithium (2.5 M, 64.4 mL, 161 mmol 2.3 eq.) and then stirred for 30 minutes. A solution of #210 (15.4 g, 70 mmol, 1 eq.) in tetrahydrofuran (150 mL) was added dropwise at −65° C. and then the solution was stirred for 2 hours at this temperature. The reaction was quenched by saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (Gradient: 10 to 16% ethyl acetate in petroleum ether) to afford #211 (7.3 g, 32%, over two steps) as yellow solid. LC-MS (Protocol Z): m/z 326.2 [M+H+], retention time=0.88 minutes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH2:9])[CH3:8].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([C:22](=O)[CH3:23])[C:18]([O:20][CH3:21])=[O:19].C(O)(=O)C>CO>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7](/[N:9]=[C:22](\[CH3:23])/[CH:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])[C:18]([O:20][CH3:21])=[O:19])[CH3:8]
Reactant: CC(N)C1COCCO1
Reactant: COC(=O)C(C(C)=O)c1ccccc1Br
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(/C(C)=N/C(C)C1COCCO1)c1ccccc1Br
Reaction time: 8 h

Procedure:
To a solution of 1-(1,4-dioxan-2-yl)ethanamine (2.5 g, 19 mmol) in methanol (100 mL) was added methyl 2-(2-bromophenyl)-3-oxobutanoate (5.4 g, 20 mmol) and acetic acid (1.8 g, 30 mmol). The resulting reaction system was warm to reflux and allowed to stir overnight. The reaction mixture was concentrated and purified by column chromatographed on silica gel (eluted: dichloromethane/methanol 50:1→20:1→5:1) the title compound (1 g, 14%) as a brown solid. LCMS (M+H+) m/z: calcd. 383.07. found 384.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[CH3:30][N:31]([CH3:51])[S:32]([CH3:50])(=[N:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)=[O:33]>O1CCOCC1>[OH:21][C@H:20]1[C@H:16]2[O:15][CH2:14][C@@H:13]([O:12][C:10]3[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]4=[N:6][C:7]([C:38]5[CH:37]=[CH:36][C:35]([N:34]=[S:32]([CH3:50])([N:31]([CH3:30])[CH3:51])=[O:33])=[CH:40][CH:39]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:11]=3)[C@H:17]2[O:18][CH2:19]1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Reactant: CN(C)S(C)(=O)=Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: C1COCCO1
Product: CN(C)S(C)(=O)=Nc1ccc(-c2nc3c(cc2Cl)nc(O[C@@H]2CO[C@H]4[C@@H]2OC[C@H]4O)n3COCC[Si](C)(C)C)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N,N-dimethyl-N′-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=624 [M+H]+.