Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH3:20])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:22]1[CH:28]=[CH:27][C:25]([OH:26])=[CH:24][C:23]=1O.[C:30]1(C)[CH:35]=CC(S(Cl)(=O)=O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].IC>CCOCC.CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:30]3[CH:31]=[CH:32][C:23]4[C:22](=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=4)[CH:35]=3)=[C:14]([O:19][CH3:20])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: COc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1-c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 70 %

Procedure:
4-Bromo-3-methoxyphenyl 4-methylbenzenesulfonate A mixture of 4-bromo-resorcinol (4.92 g, 26.0 mmol), p-toluenesulfonic chloride (5.95 g, 31.2 mmol), potassium carbonate (23 g, 167 mmol), and acetone (300 mL) was refluxed for 16 hr. Iodomethane (9.89 g, 70 mmol) was added and the mixture was refluxed for an additional 12 hr. The mixture was cooled to room temperature and ether (200 mL) was added and the suspension was filtered. The filtrate was stripped of solvent and purified on a silica column (10% ethyl acetate—hexanes) to yield 6.49 g (70%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])[C:10]([CH3:12])=O>>[CH2:15]([O:14][C:9](=[O:13])[C@H:10]([CH3:12])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(Cl)cc1

Procedure:
Following General Procedure AA above and using 4-chloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:20]2[N:21]=[C:22]([CH2:37][CH2:38][CH2:39][CH3:40])[N:23]=[C:24]([NH:25]CC3C=CC(OC)=CC=3OC)[C:19]=2[NH:18][N:17]=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.FC(F)(F)C(O)=O>C(#N)C>[CH2:37]([C:22]1[N:23]=[C:24]([NH2:25])[C:19]2[NH:18][N:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:20]=2[N:21]=1)[CH2:38][CH2:39][CH3:40]
Reactant: C1CCNCC1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCCCBr)c2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(N)c2[nH]nc(CCCCCCCN3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 284.3 %

Procedure:
Triethylamine (0.085 mL, 0.608 mmol) was added to a solution of 3-(7-bromoheptyl)-5-butyl-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (150 mg, 0.203 mmol) and piperidine (0.060 mL, 0.608 mmol) in anhydrous acetonitrile (7 mL). The solution was stirred at ambient temperature for 1.5 hours. Additional piperidine (0.060 mL, 0.608 mmol) and triethylamine (0.085 mL, 0.608 mmol) were added to the reaction mixture and stirring at ambient temperature was continued for 17 hours. The reaction mixture was evaporated in vacuo to yield a clear oil. The oil was partitioned between ethyl acetate (20 mL) and water/brine (1:1, 5 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in vacuo to yield a clear oil. The oil was dissolved in trifluoroacetic acid (3 mL, 38.9 mmol) and heated at 60° C. for 3 hours. The reaction mixture was evaporated in-vacuo and the residue was dissolved in 3:1 chloroform:IPA (20 mL) and washed with aqueous sodium hydroxide (0.1M, 5 mL). The organic phase was separated using a hydrophobic frit and the aqueous back extracted with 3:1 chloroform:IPA (20 mL). The combined organic extracts were evaporated in-vacuo to yield a yellow oil (215 mg). The oil was dissolved in MeOH:DMSO (1:1) (3×1 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in-vacuo to yield a brown oil (88.2 mg). The oil was dissolved in MeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method A). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a white solid (40.5 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>CN(C=O)C>[CH2:13]([NH:16][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:14]=[CH2:15]
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
In DMF was dissolved 1.50 g (6.8 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 917 mg (16.1 mmol) of allylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.25 g (yield: 76.2%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:12])[C@@H:9]([OH:11])[CH3:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[OH:11][C@@H:9]([CH3:10])[CH2:8][O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: C[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)O)cc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
Triethylamine was added to methylene chloride solution of (2S)-propane-1,2-diol, and then methylene chloride solution of p-toluenesulfonyl chloride was added thereto at −20° C. and stirred at room temperature for 18 hours to obtain (2S)-2-hydroxypropyl-4-methylbenzene sulfonate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9][CH2:10][C:11](=[O:13])[CH3:12]>>[Cl-:9].[C:11]([CH2:12][N+:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)(=[O:13])[CH3:10]
Reactant: CC(=O)CCl
Reactant: CSc1ccncc1
Product: CSc1cc[n+](CC(C)=O)cc1
Product: [Cl-]

Procedure:
The starting material may be prepared as follows: Reaction of 4-methylthiopyridine with 5 equivalents of chloroacetone at 40°-50° for 18 hours gave 1-acetylmethyl-4-methylthiopyridinium chloride. n.m.r. in solvent B: 2.27(s, 3H); 2.71(s, 3H); 6.0(s, 2H); 7.93(d, 2H); 8.5(d, 2H). Oxidation of this compound with a slight excess of metachlorpenbenzoic acid in CH2Cl2 /TFA at 0° to ambient temperature gave 1-acetylmethyl-4-methanesulphinyl pyridinium chloride. n.m.r. in solvent B: 2.32(s, 3H); 3.01(s, 3H); 5.84(s, 8.5(d, 2H); 9.0(d, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH3:18])[C:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.[H][H].I[CH3:35]>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:35])[C:11]([N:13]2[CH2:17][C:16]([CH3:18])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CI
Reactant: CC1(c2ccccc2)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)N1CC(C)(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a 100 ml round bottomed flask was added 0.40 g (0.01 mole) of 60% sodium hydride. The sodium hydride was washed twice with hexane and 10 ml of dimethylformamide was added. Then, 2.1 g (0.05 mole) N,3-bis-(4-chlorophenyl)-4-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 2) was added portionwise. After hydrogen evolution ceased 1 ml of iodomethane was added and the mixture was stirred for 1 hour. The reaction mixture was partitioned between ether and water and the organic layer dried, filtered, concentrated, and chromatographed yielding 1.5 g of N,3-bis-(4-chlorophenyl)-N,4-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide. Mp 132°-135° C. NMR and IR data were consistent with the structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11]([Cl:12])=[N:10][C:8]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:13]=[C:14]([Cl:15])[N:7]=[C:8]([N:1]2[CH2:6][CH2:5][N:4]([C:8]3[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([Cl:12])[N:10]=3)[CH2:3][CH2:2]2)[N:10]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)nc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Piperazine (8.0 g, 92.9 mmol) is added over a 20 minute period to a mixture of 34.3 g (186 mmol) of cyanuric chloride, 19.7 g of sodium carbonate, 80 ml of water and 200 ml of toluene maintained at a temperature of 5°-10° C. The reaction mixture is stirred for 3 hours at ambient temperature. The precipitate is filtered and washed with water and toluene to obtain 26.0 g (73% yield) of N,N'-bis-(2,4-dichloro-1,3,5-triazin-6-yl)piperazine.
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]([CH3:19])[C:12]=3[CH:20]=2)C(C)=CC=1.Cl.NO.C(N(CC)CC)C>C(O)C.O>[NH2:3][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]([CH3:19])[C:12]=2[CH:20]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)N(C)C(=O)CCC2
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CN1C(=O)CCCc2ccc(N)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 889.6 %

Procedure:
8-(2,5-Dimethyl-pyrrol-1-yl)-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (175 mgs, 0.065 mmol) was treated with hydroxylamine hydrochloride (20 eq), triethylamine (10 eq) in ethanol/water (4:1, 6 mL) and heated to 80° C. overnight. The mixture was concentrated, partitioned between EtOAc and water, dried (MgSO4) filtered and concentrated. The mixture was stirred 2 h with excess 1N HCl, neutralized to pH 7 with 1 NaOH, partitioned between EtOAc and water, dried (MgSO4) filtered and concentrated to give 8-Amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (110 mgs, 58%). 6.95 (d, J=7.8 Hz, 1H), 6.50-6.47 (m, 2H), 3.67 (br s, 2H), 3.30 (s, 3H), 2.61-2.57 (m, 2H), 2.32-2.28 (m, 2H), 2.11-2.08 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12].[OH-].[K+]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Yield: 87.5 %

Procedure:
2-(4-Methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole), 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole) and potassium hydroxide (1.4 g, 0.025 mole) were added to benzene (60 ml), and dicyclohexyl-18-crown-6 (0.2 g) was added thereto, followed by reaction at 60° C. for 10 hours. The reaction mixture was washed with water and concentrated, and the precipitated crystals were recrystallized from 95% ethanol to obtain 4.5 g of 4-[2-(4-methylphenyl)ethoxy]-nitrobenzene (VI) as white crystals (yield, 87.5%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH:15]([CH3:19])[CH2:16][CH2:17]O)[CH2:10]3)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O.[OH-].[Na+].ClCCl>C(Cl)(Cl)Cl>[Cl:24][CH2:17][CH2:16][CH:15]([N:11]1[CH2:12][C@H:13]2[C@:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=3)([CH2:14]2)[CH2:10]1)[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CC(CCO)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(CCCl)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-butanol (Preparation 19, 130 mg) in chloroform (4 mL), thionyl chloride (0.87 mmol) was added and the mixture was stirred at room temperature for 6 h. After addition of NaOH (1 M), dichloromethane was added and the organic layer was washed with Brine and dried over Na2SO4. The solution was concentrated in vacuo and the crude product purified by flash chromatography (ethyl acetate:cyclohexane=5:95) to give 106 mg of the title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][CH:7]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[C:8]([OH:10])=[O:9].BrCC=C.S(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:6][C:7]([CH2:3][CH:2]=[CH2:1])([C:11]1[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
n-Butyllithium (2.5M solution in hexanes, 61.0 mL, 153 mmol) was added slowly to a stirred, cooled (−78° C.) solution of (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 7, 19.0 g, 66.4 mmol) in tetrahydrofuran (400 mL) and the mixture was stirred at −78° C. for 2 hours. Further n-butyllithium (2.5M solution in hexanes, 8.0 mL, 20 mmol) was added slowly and the mixture was stirred at −78° C. for 20 minutes. Further n-butyllithium (2.5M solution in hexanes, 8.0 mL, 20 mmol) was added slowly and the mixture was stirred at −78° C. for 20 minutes. 3-Bromo-1-propene (8.62 mL, 12.05 g, 100 mmol) was added slowly and the mixture was stirred at −78° C. for 30 minutes, then at room temperature for 1 hour. The mixture was poured into aqueous sodium bisulfite (10%, 500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried iii vacuo to give the title compound as a colourless solid (10.59 g, 49%). 1H NMR (400 MHz, CDCl3) δ 7.82 (2H, s), 7.81 (1H, s), 5.57 (1H, m), 5.13 (1H, s), 5.10 (1H, m), 2.86 (1H, m), 2.73 (1H, m), and 1.69 (3H, s).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[C:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:33]=[C:32]([CH2:34][NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:31]=[CH:30][C:20]=2[O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:16]=[CH:17][CH:18]=1)#[N:12]>>[C:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:33]=[C:32]([CH2:34][NH:35][S:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)(=[O:38])=[O:37])[CH:31]=[CH:30][C:20]=2[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:16]=[CH:17][CH:18]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cc(CNS(=O)(=O)c3ccc(F)cc3)ccc2OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of TFA/DCM (1:3, 6 mL) was added t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (8) (51 mg, 0.10 mmol, 1 eq) and the mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo and the crude product was purified by reversed phase preparative HPLC to give 36 mg (82%) of 2-(2-(3-cyanophenyl)-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetic acid (Example 9).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CCCCCC>[C:13]1(=[C:17]([O:19][CH2:20][CH3:21])[O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15][CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(O[Si](C)(C)C)=C1CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.6 M hexane solution of n-butyllithium (2.72 mL, 4.34 mmol) was added to a solution of diisopropylamine (440 mg, 4.34 mmol) in THF (6 mL) at −78° C. over 5 minutes. The resultant solution was warmed to 0° C. for 30 min and cooled to −78° C. A solution of ethyl cyclobutanecarboxylate (464 mg, 3.62 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (0.597 mL, 4.71 mmol) was added. The mixture was warmed to room temperature over 1 h, quenched with saturated NaHCO3 (5 mL), diluted with diethyl ether (200 mL), washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated to give (cyclobutylidene(ethoxy)methoxy)trimethylsilane, which was taken to next step without further purification.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:39](/B(O)O)=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>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.O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:39]=[CH:40]/[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:20]([F:25])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Reactant: CCCCCCC/C=C/B(O)O
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: Cc1ccccc1
Product: CCCCCCC/C=C/c1ccc(C#Cc2ccc(OCCCCCCCC)cc2)cc1F
Yield: 72.4 %

Procedure:
In a four necked flask equipped with a thermometer and a stirrer, 1-(4-octyloxylphenyl)-2-(4-bromo-3-fluorophenyl)acetylene (4.8 g, 0.012 mol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), toluene (50 ml), sodium carbonate (10.6 g, 0.1 mol) and water (90 ml) were charged. Then, to the mixture, E-1-nonenyl-dihydroxyborane (2.5 g, 0.015 mol) was added and reacted at a temperature of 80° to 85° C. for 6 hours. After cooling the reaction mixture, the aqueous layer was separated off, and the organic layer was washed with water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(4-octyloxyphenyl)-2-[4-(1-trans-nonenyl)-3-fluorophenyl]acetylene (3.9 g). Yield: 73%.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.[NH4+].[OH-].O>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CC(C)Oc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Oc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-isopropoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (185 mg, 379 μmol) in dichloromethane (5.9 mL) was added trifluoroacetic acid (865 mg, 585 μL, 7.59 mmol) and the mixture stirred at r.t. for 16 h. The mixture was diluted with 25% aqueous NH4OH, dichloromethane, and water. The organic phase was separated and washed with water (2×), then concentrated in vacuo and purified by chromatography (silica, 3 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxamide (68 mg, 176 μmol, 46%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.38 (s, 1H), 7.62 (m, 3H), 6.76 (d, J=7.7 Hz, 1H), 6.54 (d, J=7.8 Hz, 1H), 6.35 (d, J=8.2 Hz, 1H), 5.18 (m, 1H), 4.07 (br. s, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.67 (dd, J=11.6, 3.8 Hz, 1H), 3.50 (dd, J=11.9. 2.3 Hz, 1H), 3.39 (m, 2H), 2.96 (s, 1H), 1.78 (m, 1H), 1.68 (m, 2H), 1.33 (dd, J=6.3, 1.7 Hz, 6H); MS (EI/CI) m/z: 388.3 [M+H].
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].N1C2C=CC=CC=2N=N1.[C:21](=O)([O:27]C1C=CC=CC=1)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>O.C1COCC1>[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of L-lysine monohydrochloride (20.0 g, 109.5 mmol) and benzotriazole (14.3 g, 120.0 mmol) in a mixture of water (66.6 mL) and THF (111.0 mL) at pH 12 was treated with t-butyl phenyl carbonate (24.3 mL, 131.4 mmol) and stirred 18 hours at 60° C. The mixture, initially 2 layers, became a clear orange solution and the product was approximately 75% (NMR).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH:16]1[C:20]2=[N:21][CH:22]=[CH:23][N:24]=[C:19]2[C:18]([NH2:25])=[N:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:25][C:18]2[C:19]3=[N:24][CH:23]=[CH:22][N:21]=[C:20]3[NH:16][N:17]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1n[nH]c2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1n[nH]c2nccnc12

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2)(0.212 g, 0.740 mmol), 1H-pyrazolo[3,4-b]pyrazin-3-amine (0.10 g, 0.740 mmol), HATU (0.281 g, 0.740 mmol) and N-methylmorpholine (0.146 ml, 1.480 mmol) in DMF (5 ml) was stirred at RT for 45 minutes. The reaction mixture was diluted with water (25 ml) and the resulting orange precipitate was filtered under vacuum and washed with water (10 ml). The solid was purified by chromatography on silica, eluting with iso-hexane:EtOAc (gradient of 0 to 100% EtOAc) to afford the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O-:12][CH2:13][CH3:14].[K+]>>[CH2:13]([O:12][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:14]
Reactant: CC[O-]
Reactant: Clc1cc2ccccc2cn1
Agent: [K+]
Product: CCOc1cc2ccccc2cn1
Temperature: 150 °C
Yield: 48.1 %

Procedure:
3-Chloroisoquinoline (3.0, 18 mmol) was dissolved in potassium ethoxide (24% in EtOH, 10.6 mL, 27 mmol) and heated to 150° C. in a sealed tube for 24 h. After cooling, the solvent was removed in vacuo and the residue treated with 1M HCl until the solution reaches a pH 3. Saturated NaHCO3 solution then added slowly to return the solution to pH 8 followed by extraction with CHCl3. The combined organics were washed with brine, dried over anhydrous MgSO4. The residue obtained from concentration in vacuo was purified by column chromatography on SiO2 (0-15% EtOAc, hex) to afford 1.5 g (48%) of 3-ethoxyisoquinoline. LCMS found 174.11 [M+H]+.