Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CNc2cccc3cccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2cccc3cccnc23)cc1
Yield: 58.8 %

Procedure:
The compound obtained in Example 16-1 (1 g) was dissolved in methanol (10 ml), and 1 mol/l aqueous solution of sodium hydroxide (10 ml) was added. The reaction solution was dissolved in THF (10 ml). After the reaction for 7 hours, the reaction solution was concentrated. The obtained residue was dissolved in water and 1 mol/l hydrochloric acid was gradually added while stirring to obtain a precipitate. The precipitate was collected by filtration through glass filter G4 and washed with water to obtain the title compound (560.1 mg) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([I:8])[CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)cc(I)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
A mixture of 3-Bromo-5-iodonitrobenzene (4.21 g, 0.0128 mol) and iron powder (3.6 g, 0.0642 mol) in glacial acetic acid (50 ml) was stirred at ambient temperature for 16 h. The reaction mixture was then filtered through a pad of celite and washed through with ethyl acetate. The filtrate was evaporated in vacuo to give a brown oil. This was re-dissolved in ethyl acetate, loaded onto a large pad of silica and eluted with ethyl acetate. The filtrate was evaporated in vacuo to afford 3-Bromo-5-iodoaniline as a brown solid (3.67 g, 96%) which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:18]=[O:19])[CH:5]=1.[CH3:21][Zn]C.[Li+].[OH-]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:18]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:21])[C:3]([OH:2])=[O:20])=[O:19]
Reactant: C[Zn]C
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C

Procedure:
Under nitrogen, Pd(dppf) (72 mg, 89 μmol) was added to a solution of 3-formyl-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (2.80 g, 8.97 mmol) in dioxane (40 mL). The mixture was stirred at rt and dimethyl zinc (11.2 g, 13.5 mmol, 12.1 mL of a 1.2M solution in toluene) was added. The mixture was stirred at 75° C. for 1 h. The mixture was cooled to rt before a 2M aq. LiOH solution (40 mL) was added. The mixture was stirred at rt for 2 h before it was concentrated. The residue was dissolved in EA and extracted with 1M aq. NaOH and water. The aq. extracts were acidified by adding 2N aq. HCl (30 mL) and then extracted with EA. The org. extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by prep. HPLC to give the title compound as a pale yellow powder (903 mg). LC-MS*: tR=0.27 min, [M−H]−=162.90; 1H NMR (D6-DMSO): δ 2.69 (s, 3H), 7.49 (d, J=7.8 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 10.29 (s, 1H), 13.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:27][NH2:28].O>ClCCCl.C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[CH3:27][NH:28][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCCl
Product: CNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.00 g) in 1,2-dichloroethane (60 mL) was added 30% solution of methylamine in ethanol (750 mg) and sodium triacetoxyborohydride (1.66 g). The mixture was stirred at room temperature for 3 hours, then small amount of water was added and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-methanol (40:1) to give the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:38])[O:37][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23][CH2:24][C:25]4[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][N:26]=4)=[N:20][C:19]=3[CH:36]=[C:15]2[O:14]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:38][C:13]1([F:12])[O:37][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23]([CH2:24][C:25]4[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][N:26]=4)=[O:6])=[N:20][C:19]=3[CH:36]=[C:15]2[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Reaction time: 0.33 h

Procedure:
21 ml of a 0.1N solution of m-chloroperoxybenzoic acid in methylene chloride are added dropwise to a suspension, cooled to -40° C., of 0.80 g of 2,2-difluoro-6[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]-benzimidazole in 10 ml of methylene chloride in the course of 10 minutes. The mixture is stirred for a further 20 minutes, during which the temperature is allowed to rise to -20° C., and 0.5 ml of triethylamine are added and the reaction mixture is poured into 40 ml of 5% strength sodium thiosulfate solution and 5% strength sodium carbonate solution. After phase separation, the aqueous phase is extracted twice more with 20 ml of methylene chloride each time; the combined organic phases are washed with a mixture of 5 ml of sodium thiosulfate solution and 5 ml of sodium carbonate solution, dried and concentrated. The residue is recrystallized from methylene chloride/diisopropyl ether. 0.62 g (75% of theory) of the title compound is obtained; decomp. 189°-190° C.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[CH3:12][Si:11]([C:9]#[C:10][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccncc1

Procedure:
Heat a mixture of 4-bromopyridine hydrochloride (1.0 eq), ethynyl-trimethyl-silane (2.0 eq), PdCl2(PPh3)2 (0.1 eq), CuI (0.2 eq) and diisopropyl ethyl amine (10 eq) in DMF at 70° C. for 18 hours. Dilute with methylene chloride, and wash with water. Dry over MgSO4, filter and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to give the title compound. MS (IS) 176.0 (M+1); TLC (20% ether in hexanes): Rf=0.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].ClC1[N:51]=[CH:50][C:49]([F:52])=[CH:48][N:47]=1>C(Cl)Cl.CS(C)=O>[F:52][C:49]1[CH:48]=[N:47][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:51][CH:50]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4ncc(F)cn4)CC3)cn2)cc1

Procedure:
The title compound (91 mg, 84%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 150, Step 2, 0.11 g, 0.25 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then K2CO3 (0.75 g) and 2-chloro-5-fluoropyrimidine (47 μL, 0.27 mmol) in DMSO (5 mL) in a manner similar to Example 80. The crude material was purified by chromatography on a silica gel column eluted with 1:15 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, 1H, J=2.7 Hz), 8.18 (s, 2H), 8.14 (d, 2H, J=8.3 Hz), 8.02 (d, 2H), J=8.3 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.45-7.35 (m, 1H), 4.80-4.70 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 3.07 (s, 3H), 3.00-2.85 (m, 2H), 2.10-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 443 (M+H).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH:18]([N:21]=[C:22]=[N:23][CH:24]([CH3:26])[CH3:25])([CH3:20])[CH3:19].C(Cl)(Cl)Cl.C[OH:32].[Na]>CN(C=O)C.C(OCC)(=O)C>[CH:18]([N:21]([C:15](=[O:17])[CH2:14][N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1)[C:22]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:32])([CH3:20])[CH3:19]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: CC(C)N=C=NC(C)C
Reactant: CO
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N(C(=O)Cn1cnc2c1c(=O)n(C)c(=O)n2C)C(C)C

Procedure:
A solution of 119 mg (0.5 mmol) theophylline-7-acetic acid in 5 ml DMF was dropped for 15-20 minutes into pre-heated at 60° C. solution of 80 μl N,N′-diisopropyl carbodiimide (DIC) in 2.5 ml DMF. The mixture was subsequently heated for 4 hours at the same temperature. After cooling the solvent was evaporated in a vacuum. The residue was dissolved in minimal amount of chloroform and purified by flash chromatography on Silicagel-60A with chloroform:methanol (98:2) as eluent. The fractions with the desired product were pooled and evaporated, yielding 82 mg (44%) from the compound Th69 as a white powder. Rf=0.68 (chloroform/methanol (9/1), Rf=0.23 (ethyl acetate). The empirical formula (F.W. 365) was confirmed by the results from LC/MS. The main molecular peak was found at 365 with a second peak at 387 for the sodium salt. The m.p. of the product was 117-120° C. The 1H-NMR Spectrum (300 MHz) was consistent with the expected structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26].C(N(CC)CC)C.[Al]>CN(C=O)C.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.[Cu]I>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: Cc1c(I)cnn1-c1ccccc1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.119 mmol), 4-iodo-5-methyl-1-phenyl-1H-pyrazole (33.8 mg, 0.119 mmol), tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.012 mmol) and copper (I) iodide (6.79 mg, 0.036 mmol) were suspended in DMF (1 mL) and triethylamine (0.033 mL, 0.238 mmol) was added. The flask was wrapped with aluminum foil and sparged with nitrogen for 5 minutes. The reaction was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-methoxy-3-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [C:1]([O:6]C[CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2](C)=[CH2:3].O=C1O[C@H:18]([C@H:20]([CH2:22][OH:23])O)C(O)=C1O.OO.C(O)(=O)[CH:27]=[CH2:28].C[N:32](C=O)C>O>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:3].[CH2:8]([NH:9][C:10](=[O:11])[CH:27]=[CH2:28])[NH:32][C:22](=[O:23])[CH:20]=[CH2:18]
Reactant: CN(C)C=O
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: C=CC(=O)O
Agent: OO
Solvent: O
Product: C=CC(=O)NCNC(=O)C=C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser, a dropping funnel and a nitrogen gas introducing device, 5 g of polysuccinimide obtained in Synthetic Example 2 and 10 g of DMF were charged and dissolved at about 60° C., and then 0.25 g of 2-methacryloyloxyethyl isocyanate was added. As a result, heat was generated. After the reaction was continued for 30 minutes, the temperature in the system was reduced to about 35° C., 1 g of a pregelatinized starch was charged. After the atmosphere in the four-necked flask was replaced by a nitrogen gas, 7.5 mg of 2,2-azobisaminodipropane dihydrochloride, 5 mg of ascorbic acid and 57 mg of an aqueous hydrogen peroxide (35%) solution were respectively dissolved in 1 g of ion exchange water. The resulting solutions were added to the above aqueous solution, and then the mixture was heated to about 60° C. and maintained for three hours ((1) first step). To the polymer obtained by this step, 25 g of acrylic acid and 25 mg of N,N′-methylenebisacrylamide were added. After the atmosphere in the four-necked flask was replaced by a nitrogen gas, 7.5 g of 2,2-azobisaminodipropane dihydrochloride, 5 mg of ascorbic acid and 57 mg of an aqueous hydrogen peroxide (35%) solution were respectively dissolved again in 1 g of ion exchange water. The resulting solutions were added to the above aqueous solution in this sequence, and then the mixture was heated again to about 60° C. and maintained at the same temperature for three hours ((1) second step). 1.2 g of hexamethylenediamine was dissolved in 20 g of ion exchange water and the resulting solution was added to the above aqueous solution, and then the reaction was conducted. Furthermore, 10.4 g of sodium hydroxide was dissolved in 30 g of ion exchange water and the resulting solution was added, thereby to neutralize carboxyl groups originating in acrylic acid ((1) third step). The resulting gel-like product was dried at 110° C. by a vacuum drier and the resulting dry solid was ground to obtain a water absorbent material of the present invention. The evaluation results of characteristics of the resulting water absorbent material are shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH:11](=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].C(OCC)(=O)C>CCCCCC>[OH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[CH:11]=[N:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10]
Reactant: O=Cc1ccccc1O
Reactant: Cc1cc(O)cc(C)c1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Temperature: 55 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 13.72 grams (0.10 mole) of 4-amino-3,5-dimethylphenol, 12.21 grams (0.10 mole) of salicylaldehyde and 250 milliliters of ethyl acetate. The resulting reaction mixture was then heated to 55° C. and stirred for 19 hours at ambient pressure. After cooling the reaction mixture to room temperature, it was filtered and concentrated under reduced pressure to give a brown oil which solidified on standing. The resulting solidified material was slurried in hexane, collected by filtration and dried to yield 19.66 grams (0.082 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol in the form of a yellow solid having a melting point of 145°-147° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30](N)(=[O:32])=[O:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N)C[NH2:44]>O.[Cu]I.O1CCOCC1>[CH3:29][S:30]([C:2]1[CH:7]=[C:6]([CH:8]([NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[NH2:44])[CH:5]=[CH:4][N:3]=1)(=[O:32])=[O:31]
Reactant: NCCN
Reactant: CS(N)(=O)=O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(Br)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(C(N)Nc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 258.4 %

Procedure:
90 mg (0.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide and 23 mg (0.24 mmol) of methanesulfonic acid amide are introduced into 5 ml of dioxane and mixed in succession with 4 mg (0.02 mmol) of copper(I) iodide, 85 mg (0.4 mmol) of potassium phosphate and 2 mg (0.02 mmol) of ethylenediamine. After 1 hour of stirring at a bath temperature of 120° C., it is diluted with 20 ml of water and concentrated by evaporation. It is then made alkaline with ammonia and shaken out three times with 25 ml each of ethyl acetate. The collected organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is made crystalline with ethyl acetate and a little hexane, stirred and suctioned off. 24 mg (26% of theory) of 2-[(2-methanesulfonyl-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide with a melting point of 214.5° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -3 °C
Reaction time: 3 h

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3598 g, 11.89 mol) was dissolved in NMP (11.108 kg) and cooled to about −3° C. A 1 M solution of NaHMDS (11.919 kg, 1.1 eq.) was added over a period of 80 minutes maintaining the temperature below 4° C. Iodomethane (1.858 kg) was added over a period of 10 minutes maintaining the temperature below 35° C. The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred for 3 hours. A 1 M solution of NaHMDS (1.2 kg) was added at 23° C. followed by iodomethane (0.188 kg). The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred overnight. The temperature was adjusted to 10° C., concentrated aqueous hydrochloric acid (6.42 L), the THF was removed by distillation at reduced pressure, the temperature was adjusted to 20° C., and water (53.3 kg) was slowly added over about 60 minutes maintaining the temperature at about 23 to 25° C. The temperature was adjusted to about 10° followed by stirring overnight. The reaction mixture was filtered, the filter cake was washed with isopropyl alcohol/water (1:1, 2×2 L), and dried in by a stream of nitrogen. The filter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C., water (20.70 kg) was slowly added over about 85 minutes maintaining the temperature at about 73 to 76° C., after 20 minutes cooled to about 11° over about 3 hours and stir overnight. Collect the solid by filtration, rinse with isopropyl alcohol/water (1:1, 2×1.7 L), and dry under a stream of nitrogen, followed by drying in an oven for 4 days to give 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10]C(OCCOS(C3C=CC(C)=CC=3)(=O)=O)=C[CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[CH2:45]([NH:47][CH2:48][CH3:49])[CH3:46].[CH2:50]1[CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:52]([O:53][CH2:54][CH2:50][N:47]([CH2:48][CH3:49])[CH2:45][CH3:46])=[CH:51][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1
Reactant: CCNCC
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Product: CCN(CC)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.338 g, 0.522 mmol) and diethylamine (1.0 mL, 9.7 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 2 hours. Additional diethylamine (1.0 mL, 9.7 mmol) added, and the reaction mixture was stirred at 80° C. in a sealed tube for 2 hours. A third portion of diethylamine (1.0 mL, 9.7 mmol) was added to the reaction mixture, and it was stirred at 80° C. in a sealed tube for 30 hours. The reaction mixture was then solvent evaporated and partitioned in ethyl acetate and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 20 minutes yielded {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-diethyl-amine as a light brown semi-solid (0.278 g, 97.2%). It was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 82° C. for 14 hours. The result was the hydrochloride as a brown foam (0.275 g); Mass Spectrum (+EI, [M+H]+) m/z 548. 1HNMR (500 MHz, DMSO-d6): δ9.86-9.88 (s, 1H), 8.72-8.75 (m, 1H), 8.56 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m. 1H), 7.57-7.63 (m, 2H), 7.29 (d, 1H, J=2.20 Hz), 7.24-7.26 (m, 1H), 7.15-7.21 (m, 3H), 7.03 (d, 1H, J=7.68 Hz), 5.73 (s, 2H), 4.35-4.38 (m, 2H), 3.49 (d, br, 2H, J=4.52 Hz), 3.14-3.25 (m, 4H), 1.19-1.23 ppm (m, 6H). Elemental Analysis for C30H30ClN3O3S.1.00 HCl.0.55 mol H2O: Calcd: C, 60.61; H, 5.44; N, 7.07; Found: C, 60.21; H, 5.44; N, 6.73.