Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[CH:2].C1C(=O)N([Br:20])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:20][C:2]#[C:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C#CBr)cc1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-ethynylbenzoate (50 g, 0.31 mol) in acetone (750 mL) was added AgNO3 (5 g, 29.7 mmol) and the reaction mixture was stirred for 1 hr. NBS (61.2 g, 0.34 mol) was added and the reaction mixture was stirred at room temperature for 20 hr, filtered and concentrated under reduced pressure. The residue was diluted in EA, and washed with iced 20% H2SO4. The organic layer was washed with water and brine, dried (Na2SO4), filtered, concentrated under reduced pressure to give a residue, which was recrystallized from MeOH (1 mL/4 g) to yield methyl 4-(bromoethynyl)benzoate (INT-1.4) as an off-yellow solid (67 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].Cl[C:24]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:25]=1[C:26](OC)=[O:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:34]([C:31]1[CH:30]=[C:25]2[C:24](=[CH:33][CH:32]=1)[N:6]1[N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]1[NH:1][C:26]2=[O:27])([O-:36])=[O:35]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 25.7 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (220 mg, 0.75 mmol), methyl 2-chloro-5-nitrobenzoate (160 mg, 0.75 mmol) and K2CO3 (155 mg, 1.13 mmol) in DMF (10 mL) was heated to 80° C. for 16 hr under N2. The reaction was poured into water (30 ml), and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to a residue, which was purified by a silica gel column eluting with 10% to 50% EA in PE to afford 85 mg (27.3%) of 7-nitro-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI, m/e) [M+1]+ 442.1.
Reaction SMILES: O[Li].O.[F:4][C:5]1([F:15])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([NH2:14])[C:7]=2[O:6]1.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[C:20]=1Cl)([O-:18])=[O:17].Cl>CS(C)=O.O>[F:15][C:5]1([F:4])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][C:20]3[C:21]([C:28]([F:30])([F:31])[F:29])=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])[C:7]=2[O:6]1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]O
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cccc3c2OC(F)(F)O3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
20.8 g of LiOH.H2O are added at 0° C. to a solution of 24.5 g of 2,2-difluoro-4-amino-1,3-benzodioxole in 70 ml of dimethyl sulfoxide. The mixture is then stirred for 20 minutes. Subsequently, a solution of 38.3 g of 2,4-dinitro-6-trifluoromethylchlorobenzene in 70 ml of dimethyl sulfoxide is added, and the resultant reaction mixture is stirred at 0° C. for 20 minutes and then heated to room temperature. After 5 hours, the mixture is poured into 350 ml of water, acidified with dilute hydrochloric acid and extracted several times with diethyl ether. The combined ether phases are washed three times with a 5 % solution of sodium carbonate and then with 5 % hydrochloric acid and dried over sodium sulfate, and the solvent is evaporated off in vacuo. The residue comprises 51.6 g of orangebrown crystals which are recrystallised in toluene. Yield: 41.6 g; melting point: 144°-146° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH2:16][N:17](C(C)C)C(C)C.Cl.C(N)C>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][CH2:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Ethylamino-3-nitro-benzoic acid methyl ester (8.3 g) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (10.0 g), DIEA (1.6 mL) and ethylamine hydrochloride salt (4.5 g) in DMF (50.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl.[N:10]([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[N:10]1
Reactant: Nc1ccccc1S
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2snnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a mixture of 2-aminobenzenethiol (1.00 g, 7.99 mmol) in water (8 mL) was added aqueous 12 N hydrochloric acid (2 mL, 20 mmol) slowly at rt. Sodium nitrite (827 mg, 12.0 mmol) was then added slowly at rt. THF (4 mL) was added for solubility, and the reaction was stirred at rt for 30 min. The solution was neutralized with saturated aqueous potassium carbonate, and the material was extracted with DCM and saturated aqueous sodium bicarbonate. The organic layer was purified via column chromatography (1% EtOAc:heptane) to afford 850 mg (78%) of the title compound as an orange liquid. 1H NMR (400 MHz, CDCl3): δ 7.63-7.73 (m, 2 H), 8.12 (dt, J=8.3, 0.9 Hz, 1 H), 8.66 (dt, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:28])([F:29])[F:15])=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2ccccc2C(F)(F)F)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=402.04.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH:18]([CH3:19])[CH:17]([CH2:20][CH3:21])[CH2:16][CH:15]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[O:14]2)[CH2:8][C:7]1=[O:27])(=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:29][CH:30]=[CH:31][CH2:32][O:33][NH2:34]>C(O)C.C([O-])(=O)C.[Na+]>[Cl:29][CH:30]=[CH:31][CH2:32][O:33][NH:34][CH2:4][CH2:3][CH2:2][CH:1]=[C:6]1[C:7](=[O:27])[CH2:8][CH:9]([CH:13]2[CH:18]([CH3:19])[CH:17]([CH2:20][CH3:21])[CH2:16][CH:15]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[O:14]2)[CH2:10][C:11]1=[O:12]
Reactant: CCCC(=O)C1C(=O)CC(C2OC(OCC(C)C)CC(CC)C2C)CC1=O
Reactant: NOCC=CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC1CC(OCC(C)C)OC(C2CC(=O)C(=CCCCNOCC=CCl)C(=O)C2)C1C
Temperature: 25 °C

Procedure:
10.2 parts by weight of 2-butyryl-5-(3-methyl-4-ethyl-6-isobutoxytetrahydropyran-2-yl)-cyclohexane-1,3-dione were dissolved in 100 parts by volume of ethanol, and 2.42 parts by weight of sodium acetate and 3.86 parts by weight of O-(3-chloroallyl)-hydroxylamine hydrochloride were added. The mixture was stirred for several hours at room temperature and then poured into ice-water, and the resulting mixture was extracted with methylene chloride. The methylene chloride phase was evaporated off, leaving 11.1 parts by weight of 2-(3-chloroallyloxyaminobutylidene)-5-(3-methyl-4-ethyl-6-isobutoxytetrahydropyran-2-yl)-cyclohexane-1,3-dione as a yellow oil of refractive index nD22 1.5129.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:5])=[O:4].S(OC)(O[CH3:27])(=O)=O.O>CN(C=O)C>[CH3:27][N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.15 g (3.75 mmol)) in 3.0 ml of DMF, 2′-nitro-p-toluenesulfonanilide (1.00 g (3.42 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.4 ml (4.22 mmol)) was added dropwise. After 2 hour's stirring, water was added to bring about separation of crystals. The resulting crystals were filtered, washed with water, dried and subjected to silica gel column chromatography with ethyl acetate-hexane (1:2 to 1:1) as eluent to give 0.93 g (89%) of N-methyl-2′-nitro-p-toluenesulfonanilide (Compound No.38) as pale yellow crystals.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=4)[O:21][N:20]=3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccc(F)cc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(4-fluoro-phenoxy)-phenyl)acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Manufacturing Example 141-1-3 and 3-ethynyl-pyridine-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (105 μL, 0.750 mmol) under nitrogen atmosphere at room temperature, which was stirred for 16 hours at room temperature. Water was added at room temperature to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1→ethyl acetate) to obtain the title compound (38.1 mg, 33.7%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:18]=2[N:17]=[CH:16][C:15]([O:19][CH3:20])=[CH:14]3)=[CH:4][CH:3]=1.[C:21]1([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([NH2:37])=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([NH:37][C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:28][N:29]=4)=[N:7][CH:6]=3)=[CH:10][CH:11]=[N:12]2)=[N:17][CH:16]=1
Reactant: Nc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1cnc2c(Oc3ccc(Br)nc3)ccnc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)nc3)ccnc2c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a nitrogen purged sealed tube was added toluene (1.5 mL), purged the solvent with nitrogen for 5 minutes and sealed the tube. To the tube was added 8-(6-bromopyridin-3-yloxy)-3-methoxy-1,5-naphthyridine (0.100 g, 0.301 mmol), 4-phenylphthalazin-1-amine (0.080 g, 0.361 mmol), sodium tert-butoxide (0.072 g, 0.753 mmol), and the tube was again purged with nitrogen and sealed. Added tBu X-phos (0.013 g, 0.030 mmol), tris(dibenzylideneacetone)dipalladium (o)(0.007 g, 0.008 mmol), purged the reaction with nitrogen, sealed, heated the tube to 100° C., stirring for 24 h. The reaction was cooled to RT, filtered through pad of silica gel, washed with 100% CH2Cl2:MeOH(90:110)/CH2Cl2 and concentrated. The crude was purified using reverse phase chromatography, extracted the concentrated product fractions into DCM, washed the organic layer 1× with sodium carbonate, 1×H2O, dried with Na2SO4, filtered solution through fritted funnel, and concentrated the filtrate to afford N-(5-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-2-yl)-4-phenylphthalazin-1-amine as light yellow solid. MS [M+H]=473; Calc'd 472.5 for C28H20N6O2.
Reaction SMILES: C1(O)C=CC=CC=1.OC1C=[C:11](C=CC=1)[C:12]([OH:14])=[O:13].F.B(F)(F)F.[OH:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:28]>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[C:12]([OH:14])(=[O:13])[CH3:11].[C:12]([OH:14])(=[O:13])[CH3:11].[OH:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:28]
Reactant: O=C(O)c1cccc(O)c1
Agent: F
Agent: FB(F)F
Agent: O=C(c1ccc(O)cc1)c1cccc(O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Oc1ccccc1
Product: CC(=O)O
Temperature: 0 °C

Procedure:
Ninety-four grams (1 mole) of phenol, 138 grams (1 mole) of 3-hydroxybenzoic acid, 400 ml of hydrogen fluoride (HF), and 170 grams of boron trifluoride were allowed to react for 15 hours at 0° C. under autogeneous pressure in an autoclave. Then the reactor contents were mixed in excess water/ice. After filtering and washing the resulting green solid with water to remove the remaining HF, the powder was slurried with water, neutralized with sodium bicarbonate (NaHCO3) solution until pH=8, filtered and finally washed with water. After drying at 25° C. in air for 10 hours and under vacuum at 120° C. for 12 hours, there was obtained 160 grams of a beige, crystalline solid which was determined by NMR analysis to be 3,4'-dihydroxybenzophenone. The solid was acetylated directly by refluxing 3 hours with 640 ml of acetic anhydride and one drop of concentrated sulfuric acid. The solution was added to ice/water. The resultant solid was filtered, washed with cold methanol, and dried at 60° C. under vacuum. There was obtained 150 grams of pure 3,4'-dihydroxybenzophenone diacetate as determined by NMR analysis. Its melting point was 83°-84° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:6][N:5]2[CH:16]=[N:17][N:18]=[C:4]2[CH:3]=1.N1C=CC=CC=1.[SH2:25]>C(N(CC)CC)C>[CH3:1][C:2]1[C:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[S:25])=[CH:10][CH:9]=2)=[N:6][N:5]2[CH:16]=[N:17][N:18]=[C:4]2[CH:3]=1
Reactant: Cc1cc2nncn2nc1-c1ccc(C#N)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc2nncn2nc1-c1ccc(C(N)=S)cc1

Procedure:
A 2.1 g. portion of p-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared as in Example 1) is partially dissolved in a solvent mixture of 50 ml. of pyridine plus 5.0 ml. of triethylamine. Hydrogen sulfide gas is bubbled into the reaction mixture over a 3 hour period during which time the color of the reaction mixture changes from yellow to green. A solid begins to form in the reaction mixture approximately 15 minutes after the addition of the hydrogen sulfide gas is begun. The mixture is then filtered and the yellow solid is washed with petroleum ether to afford the product of the example as a bright yellow solid, m.p. 268°-272° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[SH:15])=[N:8][CH:9]=1)([O-:3])=[O:2].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24]Cl)[CH2:18][CH2:17]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[S:15][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ClCc1ccccc1N1CCOCC1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2S)nc1
Product: O=[N+]([O-])c1ccc(-n2ccnc2SCc2ccccc2N2CCOCC2)nc1

Procedure:
1-(5-nitro-2-pyridyl)-2-mercaptoimidazole and 2-morpholinobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(5-nitro-2-pyridyl)-2-(2-morpholinobenzylthio)imidazole.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH:23]=[CH:22][C:20]3=2)[CH:15]=[N:14]1)(=O)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O.CO>[N:13]1([CH2:12][CH2:11][OH:10])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH:23]=[CH:22][C:20]3=2)[CH:15]=[N:14]1
Reactant: CC(=O)OCCn1ncc2ccc3occc3c21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCCn1ncc2ccc3occc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A 0.44 g of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran under argon atmosphere, a tetrahydrofuran (10 ml) solution containing 2.60 g of (1H-furo[2,3-g]indazol-1-yl)ethyl acetate was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was cooled in an ice bath, methanol was added to decompose excess lithium aluminum hydride, and then 0.44 ml of water, 0.44 ml of 15% sodium hydroxide aqueous solution and 1.30 ml of water were added in that order. The resulting mixture was stirred for 30 minutes, anhydrous magnesium sulfate and celite were added, followed by stirring for 30 minutes. After removal of the insoluble matter by celite filtration, the filtrate was concentrated under a reduced pressure to give 1.82 g of 2-(1H-furo[2,3-g]indazol-1-yl)ethanol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1.C(P(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd]Cl.CCOC(C)=O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Agent: Cl[Pd]Cl
Agent: CCP(CC)CC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3nc(C4=CCN(C(=O)OC(C)(C)C)CC4)cnc3N)[nH]c2c1

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (500 mg, 1.644 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (660.8 mg, 2.137 mmol), dichloropalladium; triethylphosphane (34.00 mg, 0.08220 mmol) and Na2CO3 (2.466 mL of 2 M, 4.932 mmol) in DMF (5.000 mL) were heated to 130° C. for 60 min in a microwave. EtOAc was added and the organic phase washed with saturated aqueous Na2CO3, dried (MgSO4) and concentrated in vacuo. The mixture was taken through crude to the next stage. MS (ES+) 407
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(C)OCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
42 ml of 3-isopropoxypropylamine was added to 21 g (0.15 mol) of 1-fluoro-4-nitrobenzene. As the reaction is exothermic, the temperature was maintained at 90° C. by cooling slightly. After 30 minutes, the reaction was complete. The medium was poured onto ice, and an oil appeared. This oil was extracted with ethyl acetate, and the organic phase is washed with water and dried over sodium sulfate. After the oil was evaporated to dryness, 35 g of a yellow oil were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl.O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cc(Br)cc(F)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution 4-bromo-2-fluoro-6-methoxy-benzoic acid (2.5 g, 10.0 mmol) in dichloromethane (30 ml) is added oxalyl chloride (1.04 ml, 12.0 mmol) added drop wise at 0° C. followed by addition of a catalytic amount of dimethylformamide. The mixture is stirred at the same temperature for 2 h. The solution is added via a cannula to a mixture of 4-chloro benzyl amine (1.7 g, 12.0 mmol) and triethyl amine (4.2 ml, 30.0 mmol) in dry tetrahydrofuran (50 ml) at 0° C. After stirring at room temperature for 16 h the mixture is diluted with dichloromethane (50 ml) and washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-benzamide (2.8 g, 7.52 mmol, 74%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:24]3[CH2:27][CH2:26][CH2:25]3)[N:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH:24]1([C:16]2[N:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[C:18]3=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[N:15]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(C3CCC3)n3ccnc(N)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(8-amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300 mg, 1.12 mmol) in 1,4-dioxane (5 mL) was added HCl (4M solution in dioxane, 10 ml) at 10° C. The resulting mixture was stirred at rt. for 3 hr. The solvent was removed under reduced pressure and the resulting residue was used for next step without any further purification. MS (ES+): m/z: 270.13 [MH+], HPLC: tR=1.62 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:33])([F:34])[F:35])[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2ccccc2C(F)(F)F)n1
Yield: 45.5 %

Procedure:
A mixture of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (70 mg, 0.2 mmol), 2-hydroxybenzotrifluoride (34 mg, 0.21 mmol) and potassium carbonate (31 mg, 0.22 mmol) in 5 ml acetonitrile was refluxed overnight. Water was added to the mixture. The product was extracted with ethylacetate, concentrated and purified by trituration with diethyl ether to give the title compound as colorless solid (43 mg, 45%).