Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:4]([I:10])[CH:5]=1
Reactant: OC1CCNCC1
Reactant: Fc1cc(I)c(CBr)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC1CCN(Cc2cnc(F)cc2I)CC1
Temperature: 80 °C

Procedure:
Combine 5-(bromomethyl)-2-fluoro-4-iodopyridine (0.2 g, 0.63 mmol), piperidin-4-ol (0.192 mg, 1.9 mmol), and diisopropylethylamine (0.22 mL, 1.27 mmol) in acetonitrile (3.0 mL). Heat the reaction mixture at 80° C. for 2 h and cool to RT. Remove the organic solvent to give crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol. Combine crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol (0.63 mmol), N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-5-fluoro-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (0.15 g, 0.32 mmol, sodium carbonate (0.102 g, 0.96 mmol), 2-(di-tert-butylphospho)biphenyl (0.006 g, 0.06 mmol) and Pd(dppf)Cl2 (0.026 g, 0.1 mmol) in THF (3 mL) and water (1 mL). Heat the mixture at 120° C. for 10 min in a microwave reactor. Pour the crude reaction mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Purify by reverse phase chromatography (28% isocratic at 85 mL/min for 8 min on a 30×75 mm, 5 mm, C18 ODB MS XBridge™ column, Solvent A: water with 0.01 M ammonium bicarbonate, Solvent B: acetonitrile) to afford the title compound (91 mg, 52%). MS (ES) m/z 549 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:12]1[CH:11]=[C:10]([NH2:9])[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1cc(N)ccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 62.5 %

Procedure:
Sodium hydride (159 mg, 60% mineral oil dispersion, 3.98 mmol) was placed in a dried flask under a nitrogen atmosphere, followed by sequential addition of anhydrous toluene (10 ml) and 2-dimethylaminoethanol (177 mg, 2.0 mmol) with a syringe. After the resulting mixture was stirred at room temperature for 40 minutes, 4-amino-2-chloropyridine (203 mg, 1.59 mmol) was added, followed by heating to reflux for 16 hours. The reaction mixture was cooled, which was subsequently added dropwise slowly onto ice water, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, to obtain a crude product as a pale brown solid (180 mg).
Reaction SMILES: CN([CH:4]=[O:5])C.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:4]=[O:5])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.47 M) solution of 6-bromo-1H-indole (1 eq.) was added at 0° C. phosphorus oxychloride (1.2 eq.). The resulting solution was warmed to RT and stirred at RT for 16 h. The resulting solution was re-cooled to 0° C. and then carefully added NaOH (2 M aq. solution, 2.8 eq.). After stirring at RT for another 2 h, the crude reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→EtOAc) afforded the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH3:22])[N:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(Br)c1ccccn1
Reactant: CCOC(=O)c1cc(C=O)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=O)nn1C(C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a mixture of 5-formylpyrazole-3-carboxylic acid ethyl ester (5.42 g) and anhydrous dimethyl formamide (80 ml), 1.41 g of 60% sodium hydride oil suspension were added at 0° C. After 30 minutes, 6.30 g of 2-(1-bromoethyl)pyridine were added at 0° C. The mixture was stirred overnight at room temperature and 120 ml of water was added thereto. The mixture was extracted with ethyl acetate (3×300 ml). The combined organic solution was dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel, Hex/EtOAc 2/1) to afford 4.0 g of 3-formyl-1-(1-(2-pyridinyl)ethyl)pyrazole-5-carboxylic acid ethyl ester as a viscous oil. NMR: 1.33 (t, 3H), 2.01 (d, 3H), 4.29 (m, 2H), 6.73 (q, 1H), 7.40 (s, 1H, 4-pyrazolyl H) 7.06, 7.19, 7.63, 8.57 (4 m, 4H, pyridyl H's), 10.04 (s, 1H, CHO). Also obtained was 535 mg of 5-formyl-1-(1-(2-pyridyl)ethyl)pyrazole-3-carboxylic acid ethyl ester as a viscous oil. NMR: 1.41 (t, 3H), 2.05 (d, 3H), 4.42 (q, 2H), 5.51 (q, 1H), 7.46 (s, 1H, 4-pyrazolyl H), 7.07, 7.17, 7.61, 8.54 (4 m, 4H, pyridyl H's), 9.88 (s, 1H, CHO).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O>[N:1]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1CCNC1
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of pyrrolidine (17 mL, 237 mmol) in 20 mL of H2O at room temperature was added p-flourobenzenesulfonyl chloride (15 g, 79 mmol) in portions over a 5 minute period. After 1 hour, the solution was diluted with 100 mL of H2O and extracted with ethyl acetate (3×50 mL). The organic was dried (Na2SO4) and concentrated in vacuo to give 12.3 g (72%) of 4-(pyrrolidinosulfonyl)-flourobenzene as a colorless oil that solidified on standing. This material was used in the following reaction without further purification. MS.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[Br:11]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)c1noc(N)c1Br
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-tert-butylisoxazole was prepared from 5-amino-3-tert-butylisoxazole and N-bromosuccinimide in 64% yield as described in Example 40a.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[I-].[K+].C1(=O)[O:30][CH2:29][CH2:28]O1>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:28][CH2:29][OH:30])=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:12][CH2:13][OH:16])=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc(OCCO)cc1)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Temperature: 145 °C
Reaction time: 6 h

Procedure:
A 500 ml round bottom flask is equipped with a mechanical stirrer, thermometer and condenser. Add 50 grams 1,1,1-tris(4-hydroxyphenyl)ethane, 100 grams DMF, 0.5 g. potassium iodide and 47.4 grams of ethylene carbonate. Heat to 145° C. and hold for 6 hours. Add 200 g. ethyl acetate and wash the organic portion four times with 150 g. saturated brine. Strip the solvent from the mix on a rotary evaporator. The yield of tan solid is 78 grams. Recrystallize this crude product by dissolving in 300 g. boiling ethyl acetate and allowing to cool slowly. Collect 70.3 grams of a tan solid; the mp=78-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[N:9]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O>CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[N:9]2)=[C:4]([NH2:14])[CH:3]=1
Reactant: Cc1nnnn1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Cc1nnnn1-c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 1-(4-bromo-2-nitro-phenyl)-5-methyl-1H-tetrazole (1.13 g, 3.98 mmol) in methanol (40 mL, not completely dissolved in methanol even at hot conditions) was treated sequentially with ammonium chloride (3.19 g, 59.7 mmol), zinc dust (2.60 g, 39.8 mmol), and water (20 mL). Initially after the addition, the reaction was exothermic. The reaction mixture was then stirred for 1 h at 25° C. The reaction mixture was then filtered, and the residue was washed with methanol (50 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 5-bromo-2-(5-methyl-tetrazol-1-yl)-phenylamine (0.90 g, 97%) as a white solid: EI-HRMS m/e calcd for C8H8BrN5 (M+) 252.9963, found 252.9962.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][CH2:25][C:26]4[N:30]=[CH:29][NH:28][CH:27]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: NCCc1c[nH]cn1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCc1c[nH]cn1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with histamine (0.16 g, 1.4 mmol). Purification using silica gel, eluting with 9:1 CH2Cl2 /MeOH, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 118 as a white solid (m.p. 190-191° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20]([O:24][C:25](ON=C(C1C=CC=CC=1)C#N)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25]([N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][CH2:11]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
1-(Ethoxycarbonylmethyl)-piperazine (5.00 g, 29.0 mmol) is dissolved in 35 mL of 50% aqueous dioxane. Triethylamine (4.41 g, 43.5 mmol) is added followed by 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (7.86 g, 31.9 mmol). The reaction is stirred for 14.5 hours at ambient temperature, then poured onto water and extracted with ethyl acetate (2×100 mL). The combined organic extracts are washed with water (3×100 mL), brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (20%→50% ethyl acetate in hexanes) affording the desired product as an oil. CIMS: MH+ 273.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2ccc(OCc3ccccc3)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccccc3)cc2n1
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of 534 mg (1.8 mmol) of 7-benzyloxy-4-chloro-2-methyl-quinoline and 3.77 ml (45 mmol) pyrrolidine was heated at 80° C. (oil bath temperature) under an argon atmosphere for 23 h after which time the reaction was completed according to HPLC analysis. The reaction was partitioned between EtOAc and water, the aqueous layer was extracted once with EtOAc, the combined organic layers were washed with water then saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (19:1:0.05) as eluent. Combination of the purified fractions and concentration in vacuo gave 430 mg (74.5%) of the 7-benzyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown solid. ISP mass spectrum, m/e: 319.4 (M+1 calculated for C21H22N2O: 319).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:32]1([CH2:38][CH2:39]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[O:31][CH2:39][CH2:38][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCN1CCCCC1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN1CCCCC1)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(2-(piperidin-1-yl)ethoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(piperidin-1-yl)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=NN=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>O1CCCC1.CO>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[N:10]=[N:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:28][C:27]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1ccccc1-c1nnc(-c2ccccc2Cl)nn1
Reactant: O=CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccccc1-c1cc(-c2ccccc2)c(-c2ccccc2Cl)nn1
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
3,6-Bis(2-chlorophenyl)-1,2,4,5-tetrazine (4.6 g) and phenylacetaldehyde (2.0 g) were dissolved in tetrahydrofuran (60 ml). A solution of potassium hydroxide in methanol (1.5 ml, 1%) was added dropwise to the solution and left to stand for 5 minutes. The solution was evaporated to 20 mls volume and was then diluted with water (50 ml). The precipitated solid was filtered, washed with water and dried to give 5.5 g of desired product, mp 176°-178° C.
Reaction SMILES: [CH2:1]1COCC1.C([Li])CCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:1]
Reactant: COc1ccc(C)cc1C(=O)c1ccccc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(c1ccccc1)c1cc(C)ccc1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a suspension of 7.58 g (21.2 mmole) methyltriphenylphosphoniumbromide in 15 ml abs. THF at room temperature within 10 minutes 17.0 ml (21.2) n-butyllithium (1.25M in n-hexane)are added dropwise. The reddish solution obtained is cooled to −78° C. and then within 15 minutes a solution of 3.70 g (16.3 mmole) 2-methoxy-5-methyl-benzophenone in 5 ml abs. THF is added. Agitation is performed initially for 20 minutes at −78° C. and for a further 8 h at room temperature. Then 80 ml water are added to the reaction mixture and extracted twice with 50 ml diethylether in each case. The purified organic phases are then dried through magnesium sulphate and the solvent is removed. Purification of the raw product obtained takes place by column chromatography on silica gel with toluene as the solvent. 3.03 g (13.5 mmole, 83%) 1-methoxy-4-methyl-2-(1-phenyl-vinyl)-benzene are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)[C:27]1=[O:52]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:51]=[C:45]7[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]7[N:43]=6)[C:27](=[O:52])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 110 °C
Yield: 74.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 141a (130 mg, 0.38 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (146 mg, 0.38 mmol), Pd(dppf)Cl2 (31 mg, 0.038 mmol), K3CO3 (105 mg, 0.76 mmol), and DMF (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1) to afford 141b as brown solid (160 mg, 74.6%). MS: [M+H]+ 567.3.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCCCOCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCOCc2ccccc2)CC1
Yield: 34.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.00 g) as starting compound and 6-benzyloxyhexyl bromide (0.75 g) were reacted and treated in the same manner as in Example 168 to give 0.45 g of 4-amino-N-((1-(6-benzyloxyhexyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)C>CN(C)C=O>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[O:13])=[CH:26][CH:27]=1
Reactant: CC(CCCCCBr)Oc1ccc(Br)cc1
Reactant: O=C1NCCN1c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2ccc(Br)cc2)CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-imidazolidinone (0.12 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 39.0 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-6-(4-bromophenoxy)heptane (0.22 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. 5 mL of saturated NH4Cl water solution and 10 mL of dichloromethane were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 7) as a white solid (0.14 g, 48%).
Reaction SMILES: CO[C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].CO.[CH2:13]([NH2:16])[CH2:14][NH2:15].Cl>O>[NH2:15][CH2:14][CH2:13][NH:16][C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C#N)CCC1
Reactant: NCCN
Agent: Cl
Solvent: CO
Solvent: O
Product: N#CC1(C(=O)NCCN)CCC1
Yield: 60.6 %

Procedure:
8.74 g (0.063 mol) of 4 and 50 mL of methanol were mixed, after which the mixture was added dropwisely into 3.77 g (4.25 mL) of ethylene diamine to form a reaction solution. The reaction solution was subjected to reaction at room temperature for 15 hours, followed by evaporation to obtain yellow oil. The yellow oil was stirred with water and was mixed with HCl to adjust pH to 2 to obtain a crude product. The crude product was purified by placing in a column (3×20 cm) filled with 100 mL of AG 50 W×8 cationic exchange resin and elutriating with water and HCl solution having gradient concentrations, collecting an eluent fraction of a gradient concentration from 0.5 N to 1.0 N, and followed by evaporating the eluent fraction to obtain 6.37 g (0.038 mol, 60.49%) of 5.
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:25](O)=[O:26])=[CH:23][N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:34]1([NH:37][C:25]([C:22]2[S:21][C:20]([NH:19][C:12]3[N:11]=[C:10]4[N:28]([CH2:29][CH3:30])[C:7]([C:5](=[O:6])[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:31]5[CH2:32][CH2:33]5)=[CH:8][C:9]4=[C:14]4[N:15]([CH3:18])[CH:16]=[N:17][C:13]=34)=[N:24][CH:23]=2)=[O:26])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)NC4CC4)s3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A, 13.97 mg, 0.030 mmol) in DMF (300 μL) was added cyclopropylamine (4.16 μL, 0.060 mmol), HATU (14.83 mg, 0.039 mmol), and Hünig's Base (15.72 μL, 0.090 mmol). The reaction mixture was stirred at rt 1 h and concentrated in vacuo: The residue was taken up in MeOH and purified by preparative HPLC. N-Cyclopropyl-2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxamide (3 mg, 19.82% yield) was isolated as a white solid.