Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.O>C(Cl)Cl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:14]([C:13]([NH:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=2)([CH3:18])[CH3:17])=[O:16])=[CH:21][C:22]=1[C:28]([F:29])([F:30])[F:31])#[N:25]
Reactant: CNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(NC(C)(C)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
The title compound was made in accordance with General Method 1. 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (1.27 g) was dissolved in DCM. EDC1-HCl (1.91 g) was added to it and the reaction mixture was stirred for 5 min at RT. 4-Amino-2-(trifluoromethyl)benzonitrile (1.00 g) was added portionwise and stirring was continued for 5 h at RT. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel) eluting with 5% MeOH-DCM to obtain 650 mg of 4-[1-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-1-methyl-ethylamino]-2-fluoro-N-methyl-benzamide, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 11.174 min, M+1: 423.
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH2:14][CH3:15])=[C:10](Cl)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH2:14][CH3:15])=[C:10]([O:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: OCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OCc2ccc(Cl)cc2)cnn(C(C)(C)C)c1=O
Yield: 76.2 %

Procedure:
To 10 ml of dry N,N-dimethylformamide was added 0.75 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and was added dropwise with a solution of 2.2 g of 2-t-butyl-5-chloro-4-ethyl-3(2H)-pyridazinone dissolved in 15 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 1.4 g of p-chlorobenzyl alcohol dissolved in 15 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at 80° C. for one hour. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sulfate and freed of solvent by distillation under reduced pressure to give a crude product. The crude product was recrystallized from hexane to obtain 2.4 g of 2-t-butyl-5-(p-chlorobenzyloxy)-4-ethyl-3(2H)-pyridazinone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]([F:21])([F:20])[S:16](Cl)(=[O:18])=[O:17]>ClCCl>[F:14][C:15]([F:21])([F:20])[S:16]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of piperazine (1 g) and triethylamine (1.78 mL) in dichloromethane (20 mL) at 0° C. was added dropwise trifluoromethanesulfonyl chloride (1.24 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into dichloromethane (2×40 mL). The combined organic layers were washed with saturated aqueous brine solution (2×40 mL), dried (MgSO4) and concentrated to afford 1-trifluoromethanesulfonyl-piperazine as a pale yellow solid (1.92 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([C:10](=[O:12])[CH3:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: CC(=O)c1cc(C)c(O)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(C(C)=O)cc1C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 1-(2,5-dimethyl-4-hydroxy-phenyl)-ethanone 14.6 g, methyl iodide 16.6 g, potassium carbonate 26.8 g and acetone 200 ml was stirred with heating under reflux for eight hours. The reaction mixture was cooled to room temperature and was filtered, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-methoxy-2,5-dimethyl-phenyl)-ethanone 15.1 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:25])=[O:26])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)OCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Yield: 44.6 %

Procedure:
A mixture of 4.0 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 19.9 g of triethylene glycol dimesylate and 3.6 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 23 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography using 30% ethyl acetate-toluene to give 3.0 g (45% yield) of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[NH:30][C:29]5[C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][CH3:38])[C:24]=5[N:23]=4)[CH:19]=[N:18]3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[N:30]([CH3:39])[C:29]5[C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][CH3:38])[C:24]=5[N:23]=4)[CH:19]=[N:18]3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)nc2n(CCC)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)n2C)n(CCC)c1=O
Temperature: 50 °C
Yield: 85.8 %

Procedure:
A mixture of 8-{1-[1-(4-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (0.030 g, 0.057 mmol), potassium carbonate (0.016 g, 0.115 mmol), methyl iodide (0.0039 ml, 0.0639 mmol) and DMF (1 ml) was heated at 50° C. for 20 hour. The mixture was cooled to room temperature and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, and dried over Na2SO4. The solvent was evaporated and the residue obtained was triturated with hexane to obtain the title compound (0.026 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([OH:20])[CH:19]=1)[C:15]#[N:16]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:19]=1)[C:15]#[N:16]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1cc(O)cc(F)c1
Product: N#Cc1cc(F)cc(Oc2ccc(C=O)cc2F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-fluoro-5-hydroxybenzonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22].CN(C)C=O>O>[CH2:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: COc1cc(O)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(C(=O)O)c(OC)c1

Procedure:
A mixture of 4.2 g. (0.025 mole) of 4-hydroxy-2-methoxybenzoic acid, 7 g. of potassium carbonate, and 10 g. of n-butyl bromide in 100 ml. of N,N-dimethylformamide was heated at 70° C. for 24 hours. The mixture was cooled, diluted with water and extracted with diethyl ether. The ether extracts were washed with dilute sodium hydroxide solution, then washed with water and dried. The ether was evaporated and the residue heated at reflux for 4 hours in an equivolume mixture of 10 percent sodium hydroxide solution and ethanol. Evaporation followed by acidification provided the desired 4-(n-butoxy)-2-methoxy-benzoic acid (m.p. 94°-96° C. after recrystallizaiton from cyclohexane).
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][N:18]2[C:22]([CH:23]=O)=[CH:21][N:20]=[CH:19]2)=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(C(Cl)Cl)(Cl)Cl.CCOC(C)=O>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:22]([CH2:23][CH:9]3[CH2:10][C:5]4[CH:4]=[CH:3][S:2][C:6]=4[NH:7][CH2:8]3)=[CH:21][N:20]=[CH:19]2)=[CH:25][CH:26]=1)#[N:12]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: c1cc2c(s1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CC2CNc3sccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Halczenko and Hartman; Synthetic Commun., 1996, 26, 1363; 0.439 g, 2.5 mmol) in CHCl2CHCl2 (15 mL) was added 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (0.58 g, 2.75 mmol), 4 Å sieves and triethylamine (0.35 mL, 2.5 mmol) followed by NaBH(OAc)3 (1.59 g, 7.5 mmol). The mixture was stirred at room temperature for 16 h., the mixture was diluted with EtOAc, filtered through celite, washed with brine, dried (Na2SO4) and concentrated. The residue was stirred in 2N HCl (50 mL) for 2 h. then extracted with ether. The aqueous layer was basified with 40% NaOH solution and extracted 3× CH2Cl2 which was then washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. Chromatography (silica gel; 2.5% MeOH in CHCl3) followed by crystallization from ether afforded the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN(CCOc1ccc(N)cc1)CCc1ccc(N)cc1
Yield: 88.7 %

Procedure:
A solution of 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane (1.5 g) in ethanol (100 ml) was stirred for hours at room temperature under three atmospheres of hydrogen in the presence of Raney nickel ("Nicat 102"-Trade Mark). The reaction mixture was filtered and evaporated to dryness. The residual oil was re-dissolved in ether, filtered and evaporated to give a yellow solid (1.1 g), which was crystallised from ethyl acetate/60°-80° petroleum ether to give the title compound, (0.9 g), m.p. 73°-74°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cccc(OC)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(OC)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogen carbonate (0.77 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.23 g, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6]
Reactant: C=CCc1cc([N+](=O)[O-])c(CO)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCc1cc([N+](=O)[O-])c(CO)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
4.68 g of 3-hydroxy-6-nitro-4-(2-propenyl)benzylalcohol was dissolved in 90 ml of N,N-dimethylformamide. Thereafter, 3.71 g of potassium carbonate and 3.81 g of iodomethane were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 3.93 g of the subject compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](O)=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:43]1(OC(N(C)C)=[N+](C)C)[C:47]2N=CC=C[C:46]=2[N:45]=N1.C(CN)O>CN(C=O)C>[NH2:43][CH2:47][CH2:46][NH:45][C:28]([C:27]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:26]=1[CH2:25][NH:24][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23])=[O:29]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: NCCO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)NCCN)c(OCc1ccccc1)c2=O
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A mixture of intermediate 190, 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoic acid, (59 mg, 0.12 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HATU (76 mg, 0.2 mmol; Aldrich) in DMF (1 mL) was stirred for 20 min. To this mixture was added ethanolamine (20 mg, 0.3 mmol) and the stirring continued overnight. The mixture was concentrated in vacuo, dissolved in CH2Cl2, washed with water then dried (MgSO4), filtered, and concentrated to provide 55 mg (Yield 87%) of the title compound: LC/MS m/z 525 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([Cl:16])[CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=O)C.O.[NH2:21][NH2:22]>C(O)C>[Cl:16][C:13]1[CH:12]=[C:11]([Cl:17])[C:10]([O:18][CH3:19])=[C:9]2[C:14]=1[CH:15]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:7]=[N:8]2
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1c(Cl)cc(Cl)c2cc(C(=O)NN)cnc12
Yield: 79.5 %

Procedure:
A solution of 5,7-dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester 27 (404 mg, 1.35 mmol) and hydrazine monohydrate (1.0 g) in ethanol (10 ml) was heated under reflux for 5 hours. Upon cooling, a white crystalline solid was deposited. This was isolated via filtration, washed with ethanol, and dried, yielding the hydrazide 28 (307 mg, 80%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 10.32 (br, 1 H), 9.33 (d, J=2.4, 1 H), 8.89 (d, J=2.4, 1 H), 8.02 (s, 1 H), 4.66 (br, 2 H), 4.06 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:18]CC1.CC(C)=O.[O-]S([O-])=O.[Na+].[Na+].[OH2:32]>[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:18])([C:10]([F:11])([F:12])[F:13])[CH2:9][OH:32])=[CH:6][CH:7]=1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(c1ccc(Br)cc1)C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCC(O)(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 21 h

Procedure:
Osmium tetroxide (4 wt % solution with water, 4.3 mL, 0.70 mmol) was added to a stirring mixture of 1-bromo-4-(1-(trifluoromethyl)ethenyl)benzene (3.5 g, 14 mmol), 4-methylmorpholine N-oxide (1.8 g, 15 mmol), acetone (14 mL), and water (14 mL) at room temperature. After 21 h, Na2SO3 (8.8 g, 70 mmol) was added, the mixture was filtered. Silica gel (20 g) was added to the filtrate, and the volatiles were removed in vacuo. The residue was purified via column chromatography (5% MeOH in CH2Cl2) to afford 2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol (3.0 g) as an off-white solid.
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH2:19])[C:11]=1[C:20]#[N:21])(C)[C:6](=O)[CH3:7])C.C(O)(=[O:25])C.OS(O)(=O)=O>O>[NH2:19][C:12]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=[C:10]2[C:11]=1[C:20](=[O:25])[NH:21][C:6]([CH3:7])=[C:5]2[CH3:4]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(N)c1C#N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1[nH]c(=O)c2c(N)c([N+](=O)[O-])ccc2c1C
Temperature: 100 °C
Yield: 72 %

Procedure:
The ester from above (1.39 g, 4.56 mmol) was added to a mixture of acetic acid (20 mL), H2SO4 (3 mL) and water (2 mL), and the solution heated at 100° C. for 3 h. The cooled solution was diluted with water (30 mL), the precipitate was collected, washed with water and MeOH and dried to give 8-amino-3,4-dimethyl-7-nitro-2H-isoquinolin-1-one (0.76 g, 72%). mp>300° C.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13](B3[O:20][C:19]([CH3:22])(C)C(C)(C)O3)=[CH:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.[C:50](=[O:53])([O-])[O-:51].[Na+].[Na+]>COCCOC.O>[C:19]([OH:51])(=[O:20])[CH3:22].[C:50]([OH:51])(=[O:53])[CH3:1].[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C@@H:39]2[CH2:38][CH2:37][C@H:36]([N:28]3[C:29]4=[N:30][CH:31]=[N:32][C:33]([NH2:35])=[C:34]4[C:26]([C:13]4[CH:12]=[CH:11][C:10]([NH:9][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH3:8])=[CH:15][CH:14]=4)=[N:27]3)[CH2:41][CH2:40]2)[CH2:43][CH2:44]1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC(Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CC(Nc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-(1-phenylethyl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.070 g, 0.000235 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.000181 mol), tetrakis-(triphenylphosphine)palladium (0.012 g, 0.000011 mol) and sodium carbonate monohydrate (0.056 g, 0.00045 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(1-phenylethyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.062 g, 0.0000984 mol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]N(C)CCN(C)C.C([Li])(C)(C)C.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2c(cccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran (40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at −78° C. The mixture was stirred at −78° C. for 40 minutes. To the resulting mixture was added iodomethane (5.07 mL) dropwise and the mixture was stirred at −78° C. for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed with brine (40 mL×3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flask chromotography (silica gel, 10% methanol/dichloromethane).