Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([N:11]([C:13]2[CH:14]=[C:15]([S:19](O)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1C(Cl)=NC(Cl)=NC=1Cl.C(N(CC)CC)C.[OH-].[NH4+]>CC(C)=O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([N:11]([CH3:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([NH2:25])(=[O:21])=[O:20])[CH:14]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)c1ccc(C(C)(C)C)cc1)c1cccc(S(=O)(=O)O)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)c1cccc(S(N)(=O)=O)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A solution of 3-(4-tert-butyl-N-methylbenzamido)benzenesulfonic acid (12 mg, 35 μmol), cyanuric chloride (7.0 mg, 40 μmol), and triethylamine (6.0 μL, 40 μmol) in acetone (0.5 mL) was sealed in a glass tube and heated in a microwave oven at 120° C. for 10 min. Concentrated ammonium hydroxide (150 μL) was added, and the reaction was stirred for 6 h. The reaction was filtered, and the filtrate was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 4-tert-butyl-N-methyl-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 347.3 (M+H)+ at 2.86 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CCN(CC)CC.[CH:8](=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:8]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC=C1CCCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC1CCCCC1=O
Temperature: 50 °C
Reaction time: 23 h
Yield: 95.1 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 845 mg (0.5 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 17.8 g (100 mmole) of 2-pentylidenecyclohexanone and 50 ml of methylene chloride were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 90 kg/cm2 for 23 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography- using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 16 g (percent yield: 90%) of 2-pentylcyclohexanone as a clear yellow liquid. 1H-NMR (CDCl3)δ(ppm): 1.20 (t, 3H, J=7 Hz), 1.40 (m, 8H), 1.50-2.50 (m, 9H)
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([C:12]([O:14]CC)=O)[CH2:6]1)=[O:4].Cl.[C:20]([NH2:26])(=[NH:25])[CH2:21][CH2:22][CH2:23][CH3:24].C[O-].[Na+]>C(O)C.CO>[CH2:21]([C:20]1[NH:26][C:12](=[O:14])[C:7]2[CH2:6][N:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:17])[CH3:18])[CH2:10][CH2:9][C:8]=2[N:25]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C1CN(C(=O)C(C)(C)C)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(=O)C(C)(C)C)CC2
Yield: 67.4 %

Procedure:
A mixture of 1.3 g of ethyl 1-(2,2-dimethyl-1-oxopropyl)-4-oxo-3-piperidinecarboxylate and 0.75 g of valeramidine hydrochloride in 10 ml of anhydrous ethyl alcohol is treated with 5.3 ml of a 1M solution of sodium methoxide in methanol. The resulting mixture is stirred and heated at reflux for one hour. The reaction mixture is allowed to cool over 30 minutes then filtered. The filtrate is evaporated to a gummy residue and stirred with 40 ml of ether for 30 minutes, filtered and the cake washed with ether. The cake is dried at 56° C. under vacuum to afford 1.0 g of the desired product as a colorless solid, m.p. 167°-172° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][P:9]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)[OH:14])(=[O:12])[O:10][CH3:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:7][O:8][P:9]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)[O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)(=[O:12])[O:10][CH3:11]
Reactant: COP(=O)(OC)C(O)c1cccc(C#N)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COP(=O)(OC)C(OC1CCCCO1)c1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
3,4-Dihydro-2H-pyran (10.83 g, 128.70 mmol) and p-toluenesulfonic acid (0.34 g, 1.75 mmol) were added to a solution of [(3-cyanophenyl-hydroxy-methyl]-phosphonic acid dimethyl ester (14.10 g, 58.50 mmol) in dry toluene (195 ml) and the reaction mixture was stirred under nitrogen atmosphere at 50° C. for 3 h. The solvent was then removed under vacuum and the residue was taken up with ethyl acetate (100 ml). The organic layer was washed with a saturated NaHCO3 solution (1×100 ml), brine (1×100 ml) and dried over Na2SO4. The filtrate was evaporated to dryness to give the crude [(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic acid dimethyl ester as a yellow oil (19 g, 58.46 mmol, 100%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:33][N:25]([CH2:24][CH2:23][CH2:22][N:21]([CH3:34])[C:14]1[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:13]=1)[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(CCCN(C)c1cc(N)cc2ccoc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Benzenesulfonyl chloride (115 μL, 0.9 mmol) was added to a mixture of tert-butyl 3-[(5-amino-1-benzofuran-7-yl)(methyl)amino]propyl(methyl)carbamate (Intermediate 2; 250 mg, 0.75 mmol) in DCM (2 mL) followed by addition of pyridine (1 mL). The reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated in vacuo and the residue obtained was purified using RP-HPLC (Gilson/YMC AQ C18; 150×30 mm) to give the title compound as a beige oil (202 mg, 43% over 4 steps); HPLC 93%, RT: 2.49 min (System A); 95%, RT: 2.27 min (System B); 1H NMR (CDCl3) δ ppm 1.41 (s, 9H), 1.60-1.75 (m, 2H), 2.74 (s, 3H), 2.93 (s, 3H), 3.13-3.25 (m, 2H), 3.42-3.53 (m, 2H), 6.19-6.69 (m, 2H), 6.87-7.06 (m, 1H), 7.33-7.58 (m, 4H), 7.71-7.79 (m, 2H); MS m/z 474 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11]1(Cl)[N:16]=[C:15](Cl)[N:14]=[C:13](Cl)[N:12]=1>[OH-].[Na+].COCCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:11]1[N:16]=[C:15]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:13]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cc(Cl)cc(Cl)c1Oc1nc(Oc2c(C)cc(Cl)cc2Cl)nc(Oc2c(C)cc(Cl)cc2Cl)n1
Reaction time: 0.05 h

Procedure:
By the same procedure as in Example 1, 60 g of sodium hydroxide is dissolved at 70° C. in 1.8 liters of ethylene glycol monomethyl ether and, by the addition of 265.6 g (1.5 moles) of 2,4-dichloro-6-methylphenol, a phenolate solution is prepared into which 92 g (0.5 mole) of cyanuric acid chloride is stirred at 70° over a period of 3 minutes, causing the temperature of the reaction mixture to rise to 81° C. After half an hour of refluxing, the product is separated as in Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[C:10]3[CH:23]=[CH:24][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:8][C:9]=3[S:13](=[O:15])(=[O:14])[N:12]=2)=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCBr)cc21
Product: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCN3CCCC3)cc21

Procedure:
According to the method in example 10, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxide and Pyrrolidine were converted to yield 3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole 1,1-dioxide, MS: 419 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(F)c(F)cc1F
Temperature: 0 °C

Procedure:
In 20 ml of 80% sulfuric acid was dissolved 5.8 g of 2,4,5-trifluorobenzonitrile and the mixture was heated under reflux for 30 minutes. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was dried over sodium sulfate and the solvent was removed to yield 5.32 g of 2,4,5-trifluorobenzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1.Cl.COCCO>O1CCOCC1>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: COc1c(N)ccc2c1CCCC(=O)N2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 7-Amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (110 mg, 0.00053 mol) Isopropyl alcohol, (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (170 mg, 0.00048 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and 2-Methoxyethanol (5.3 mL, 0.067 mol) in a Radley tube, heat to 110° C. for about 4.5 h. Cool to RT and a solid came out of solution, stirred over night Filtration was followed by washing with 2-methoxyethanol to give a yellow powder. The powder was treated with saturated aq. bicarb, sonicated to break up solids and stirred for 1 h. The yellow solid was filtered and dried overnight. Isolated C as a yellow solid (131.16 mgs, 52%); MP: 248-249° C.; 1H-NMR (dmso, 400 MHz) δ 9.60 (s, 1H), 9.38 (br s, 1H), 9.15 (br s, 1H), 8.32 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 6.53-6.48 (m, 2H), 3.80-3.78 (m, 4H), 3.77 (s, 3H), 3.70 (s, 3H), 3.25-3.19 (m, 6H), 2.70-2.68 (m 2H), 2.14-2.10 (m, 2H); LC/MS: 525.36 (M+H).
Reaction SMILES: OC[C@@H](N[C:11](=[O:26])[C@@:12]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[CH3:25][C@:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:11]([OH:26])=[O:28]
Reactant: CC(C)(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 98 %

Procedure:
To a solution of Example 49A (3.78 g, 10.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.47 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C(N(CC)CC)C.[Si:13]([O:20][C@@H:21]([C@@H:23]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[NH:25][C:24]1=[O:31])[CH3:22])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:13]([O:20][C@@H:21]([C@@H:23]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[N:25]([Si:2]([CH3:4])([CH3:3])[CH3:1])[C:24]1=[O:31])[CH3:22])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C
Temperature: 25 °C

Procedure:
First 22.8 ml of trimethylsilyl chloride and then 25.1 ml of triethylamine were added dropwise to a solution of 43.1 g of (3R,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxy-2-azetidinone in 450 ml of methylene chloride, maintained at 0° to 5° C. in an ice-water bath. The mixture was stirred at room temperature for 2 hous, then again cooled to 0° to 5° C. in an ice-water bath and filtered under suction. The filtrate was concentrated under reduced pressure. The residue was mixed with 300 ml of anhydrous ether and insolubles were filtered off. The solvent was stripped off from the filtrate, giving 52.8 g of crystalline (3R,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxy-1-trimethylsilyl-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(OC)(O[CH3:33])(=O)=O>>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:33])[C:18]2=[O:28])=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Product: CCOC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using ethyl 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]-propionate and dimethyl sulphate there is obtained ethyl 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]-propionate, 1H-NMR (CDCl3, 400 MHz): 7.32 ppm (d,1H), 6.83 ppm (d,0.5H), 6.81 ppm (d,0.5H), 6.34 ppm (2s,1H), 4.53-4.72 ppm (m,1H), 4.13-4.27 ppm (m,2H), 3.50-3.59 ppm (m,3H), 1.67 ppm (d,3H), 1.18-1.28 ppm (m.3H):
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C
Yield: 53 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) was dissolved in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g), heated to 60° C. for 1 hour and then cooled to room temperature. To the above was added 3-(bromomethyl)tetrahydrofuran (0.103 g) and the reaction mixture heated at 50° C., overnight. The reaction mixture was quenched with water (25 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The combined organic phase was separated and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (97 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])[CH:22]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Reactant: Nc1cccnc1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccnc3)ccc12
Yield: 34.2 %

Procedure:
This compound was prepared according to the method of Example 15, using 58 mg (0.210 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 22 mg (0.231 mmol, 1.1 equiv) 3-aminopyridine as starting materials, to give 24 mg (34%) of white crystals: mp 133-135° C.; HRMS calcd for C20H22N4O+H: 335:1872. Found: 335.1900.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>>[N+:27]([CH:30]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)([O-:29])=[O:28]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCCCCCCCCCCCOc1ccc(C=C[N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
4-Dodecyloxybenzaldehyde (7.91 g; 27.25 mmol), ammonium acetate (1.57 g; 20.4 mmol) and nitromethane (2.57 ml; 48 mmol) are mixed together and the mixture is heated for 1.5 hours at 105° C. Cooling to 25° C. and extraction with tert-butyl methyl ether (50 ml) are then carried out, and the organic phase is dried over Na2SO4. After filtration, concentration to dryness by evaporation is carried out and the residue is suspended in methanol (80 ml). Filtration is then carried out, and the pale yellow crystals are washed with methanol and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C:21]([CH3:25])([CH3:24])[CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCOCC>[C:13]([NH:20][C:21]([CH3:25])([CH:24]=[CH:9][CH:3]1[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])[CH3:22])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: CC1(C)CCC(C)(C)C1CBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all of the magnesium has dissolved. At 0° C. a solution of N-Boc-2-amino-2-methylpropanal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue dissolves in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated as shown by thin layer chromatography. Water is added and the mixture extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.ClCCl.Cl.CN(C)CCCN=C=NCC.[CH:27]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:32][CH2:33][NH:34][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: NCCC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask was charged 3-iodo-4-methylbenzoic acid (1.4 g, 5.4 mmol), dicloromethane (4 ml), and DMF (2 ml). This mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol) was added. The reaction mixture was stirred for 10 min before 2-cyclopentylethanamine (0.47 g, 4.2 mmol) was introduced. The reaction mixture was stirred at 0° C. for 1 h, then at RT under N2 for 16 h. The reaction was partitioned between DCM (60 ml) and brine (50 mL). The aqueous layer was back exacted with DCM (4×20 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a Redi-sep pre-packed silica gel column (330 g), eluting with a gradient of 5% to 15% EtOAc in hexane, to provide N-(2-cyclopentylethyl)-3-iodo-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 358.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[O:9])[CH:3]=1
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (26.76 g; 151 mmol), obtained as described above for Intermediate 7 step 1, in anhydrous DCM (270 ml) was treated dropwise over 25 minutes with a solution of o-toluidine (13.6 ml; 126.0 mmol) and DIEA (43.4 ml; 252 mmol) in anhydrous DCM (100 mL). At the end of addition, the reaction mixture was washed with water then brine, dried over MgSO4, filtered and dried under vacuum to afford the title compound used without further purification as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.47 (1H, br s), 9.32 (1H, d, J=1.0 Hz), 8.25 (1H, d, J=1.0 Hz), 7.65-7.63 (1H, m), 7.34-7.19 (3H, m), 2.31 (3H, s). MS (ESI+): 248.0; MS (ESI−): 246.1. HPLC (Condition A): Rt 4.19 min (HPLC purity 96.0%).
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=1[OH:28])(=[O:19])=[O:18])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]=[C:38]=[O:39]>>[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:21]([OH:28])=[C:22]([NH:27][C:38]([NH:37][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([Cl:36])[C:30]=2[Cl:29])=[O:39])[CH:23]=[CH:24][C:25]=1[Cl:26])(=[O:19])=[O:18])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 54.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-[3-(tert-butoxycarbonylamino)propyl]-3-amino-6-chloro-2-hydroxybenzenesulfonamide (110 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (65 mg, 0.35 mmol) were coupled to form the desired urea (90 mg, 55%). EI-MS (m/z) 565.64, 567.74, 569.60 (M−).
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#[CH:2].[CH3:11][CH2:12][CH2:13][CH2:14][SnH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:6]1[CH2:7][CH2:8][C:3](/[CH:1]=[CH:2]/[Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH3:11])([OH:10])[CH2:4][CH2:5]1
Reactant: C#CC1(O)CCN(C)CC1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/C1(O)CCN(C)CC1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Ethynyl-1-methylpiperidin-4-ol (Exploratory Library; 3.34 g; 24 mmol) and PdCl2(PPh3)2 (337 mg; 0.48 mmol) were dissolved and stirred in THF (100 ml), cooled in a water bath to 180C, while Bu3SnH (7.6 ml; 28.8 mmol) was added dropwise within 3 minutes. The reaction mixture was stirred at room temperature for 4 hours, poured directly on a column of SiO2 and chromatographed (EtOAc/MeOH/NH3 95/5/0.5) to deliver the title compound as a greenish oil (3.45 g; 33%).