Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:11]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:46]=[C:47]1[NH:56][CH:55]=[CH:54][C:53]2[N:52]=[C:51]([C:57]3[CH:64]=[CH:63][C:60](C=O)=[CH:59][CH:58]=3)[C:50](C3C=CC=CC=3)=[CH:49][C:48]1=2>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:60]3[CH:59]=[CH:58][C:57]([C:51]4[CH:50]=[CH:49][C:48]5[C:47](=[O:46])[NH:56][CH:55]=[CH:54][C:53]=5[N:52]=4)=[CH:64][CH:63]=3)[CH2:16][CH2:17]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccn3)c2)CC1
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(n5cnc(-c6ccccn6)c5)CC4)cc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidine-1-carboxylate (300 mg, 0.9 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was dried under vacuum for a further 2 h. The residue was dissolved in a solution of triethylamine (1 mL) in CH2Cl2 (3 mL). The reaction mixture was stirred for 1 h at room temperature and sodium triacetoxyborohydride (381 mg, 1.8 mmol), 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (295 mg, 0.9 mmol) and molecular sieves were added. Stirring was continued at room temperature for 16 h and the reaction quenched by addition of methanol. The residue was purified by HPLC (phenomenex column, 35%-100% acetonitrile/water+0.1% TFA) to afford 3-phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl-1,6-naphthyridin-5(6H)-one trifluoroacetic acid salt as a yellow oil. 1H NMR (500 MHz, CD3OD) δ 8.56 (m, 3H), 8.28 (s, 1H), 8.10 (m, 1H), 7.99 (m, 1H), 7.45 (m, 1H), 7.42 (m, 5H), 7.21 (m, 3H), 7.15 (m, 2H), 6.77 (m, 1H), 4.62 (m, 1H), 4.34 (s, 2H), 3.55 (m, 2H), 3.21 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([N:32]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24]2)([CH2:21][CH3:22])/[CH:17]=[CH:18]/[C:19]#[N:20])=[CH:12][CH:11]=1>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([N:32]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24]2)([CH:17]2[CH2:4][CH:18]2[C:19]#[N:20])[CH2:21][CH3:22])=[CH:14][CH:15]=1
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of NaH (22 mg) in anhydrous DMSO (0.9 mL) was added trimethylsulfoxonium iodide (128 mg) at 0° C. and the mixture was stirred at rt for 3 h until the solution became clear. Then was added the solution of (E)-N-(1-(3-(4-chlorophenyl)-1-cyanopent-1-en-3-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42 mg) in anhydrous DMSO (0.1 mL) and the reaction mixture was stirred at 70° C. for 16 h. The solution was quenched with saturated NH4Cl solution, extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=4/1) to afford the title compound as a white solid. LC/MS m/z=559.2 [M+H]+.
Reaction SMILES: [Cl:1]C(Cl)(Cl)C=O.C(#N)C=C.[Cl:11][CH:12]([CH2:15][C:16]([Cl:20])(Cl)[CH:17]=O)[C:13]#[N:14]>O>[Cl:1][C:17]1[C:16]([Cl:20])=[CH:15][C:12]([Cl:11])=[CH:13][N:14]=1
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Reactant: O=CC(Cl)(Cl)Cl
Solvent: C=CC#N
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
A process for producing 2,3,5-trichloropyridine, which process comprises causing trichloroacetaldehyde to undergo an addition reaction, in the presence of a catalyst, with acrylonitrile, and cyclising the formed 2,4,4-trichloro-4-formylbutyronitrile of the formula I ##STR2## with the splitting-off of water, to give 2,3,5-trichloropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/I)[CH3:12].O>C(N(CC)CC)C.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>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[C:9]#[C:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:12]
Reactant: CCOC(=O)/C=C/I
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdCl2(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) and copper(I)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirred for 2 h at 50° C., whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3×20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichlorophenyl)-pent-2-en-4-ynoic acid ethyl ester in 1.1 g yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Cl)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>CN1CCCC1=O>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[N:4]=2)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]
Reactant: OCc1cccc(CO)n1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Solvent: CN1CCCC1=O
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccc(CO)n1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using 2,6-bis(hydroxymethyl)pyridine (0.11 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.11 g) in N-methylpyrrolidinone (2 mL). Yield 0.043 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]1.[O:20]1[C:24]2[CH:25]=[C:26]([C:29](Cl)=[O:30])[CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]3[NH:22][C:21](=[O:32])[O:20][C:24]=3[CH:25]=2)=[O:30])[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc2[nH]c(=O)oc2c1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1N1CCN(CCCCNC(=O)c2ccc3[nH]c(=O)oc3c2)CC1
Yield: 71.2 %

Procedure:
According to the method of Example 3, 4-[4-(2-methyloxyphenyl)piperazinyl]butylamine and benzoxazolin-2-one-6-carbonyl chloride were subjected to acylation in the presence of sodium carbonate as deacidficating agent to obtain the product. Yield: 71.2%. mp: 175-177° C. 1HNMR (ppm, DMSO-d6) δ: 1.53 (m, 4H), 2.36 (m, 2H), 2.50 (s, br., 4H), 2.94 (s, br., 4H), 3.28 (m, 2H), 3.76 (s, 3H), 6.86 (m, 2H), 6.93 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 7.70-7.74 (m, 2H), 8.42 (t, J=5.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Yield: 81 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 1.9 g of 2,4-dichloroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 2.6 g (80%) of 4-(2,4dichloro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile as yellow needles: melting point 206-208° C.; mass spectrum (m/e): M+H 332.8.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC(OC)=C(OC)C=1)=O.[C:23]1([O:31][CH3:32])[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:37][C:38]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:39]=1[C:40](Cl)=[O:41]>>[Cl:37][C:38]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:39]=1[C:40](=[O:41])[C:29]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:23]([O:31][CH3:32])[CH:30]=1
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cc(Cl)ccc2Cl)cc1OC

Procedure:
2′,5′-Dichloro-3,4-dimethoxybenzophenone was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.15 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and 2,5-dichlorobenzoyl chloride (1.9 mL, 15 mmol) with a reaction time of 3 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 3.88 g (83%) of the product as a white solid: mp 129-130° C.; 1H NMR (CDCl3) δ7.65-7.56 (m, 1 H), 7.41-7.12 (m, 4 H), 6.89-6.81 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ191.1, 154.4, 149.6, 137.9, 132.0, 130.5, 128.7, 128.0, 125.7, 110.2, 56.1, 56.0; Anal. Calcd for C15H12Cl2O3. Theoretical: C, 57.90; H, 3.89. Found: C, 57.58; H, 3.87.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(N[C:18]1[CH:27]=[C:26]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[C:25]([O:34]C(=O)CCC)=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:40])=[N:23]2)(=O)CCC.[OH2:41]>C(O)(=O)C>[C:29]([NH:28][C:26]1[C:25](=[O:34])[C:24]2[N:23]=[C:22]([CH3:40])[CH:21]=[CH:20][C:19]=2[C:18](=[O:41])[CH:27]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: O
Reactant: CCCC(=O)Nc1cc(NC(=O)CCC)c2ccc(C)nc2c1OC(=O)CCC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Yield: 77 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottomed flask equipped with a magnetic bar, 5,7-dibutyramido-8-butyroxy-2-methylquinoline (34) (prepared as described in Examples 31-34) (3.29 g., 8.25 mmol) was suspended in 122 ml of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and stirred. The stirred suspension began to dissolve but, after two hours, more solid continued to precipitate. Dichloromethane (70 ml.) was added to promote solution. The resulting two-phase solution mixture was stirred at room temperature overnight. The two-phase solution mixture was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with a 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield an orange-yellow solid. After vacuum drying, the solid weighed 1.65 g. (a yield of 77%). The product was recrystallized from ethyl acetate: mp. 188°-189° C.; 1H NMR (CDCl3) δ1.00 (3H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 1.69-1.82 (2H, m, C-7NHCOCH2CH2CH3), 2.48 (2H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 2.74 (3H, s, C-2CH3), 7.53 (1H, d, J=8.0 Hz, C-3H), 7.90 (1H, s, C-6H), 8.28 (1H, d, J=8.0 Hz, C-4H), 8.36 (1H, br. s, C-7NH); IR (KBr) vmax 3338, 3275, 2964, 2935, 2875, 1711, 1682, 1654, 1644, 1615, 1588, 1502, 1323, 1310, 1133 cm-1 ; EIMS, m/e (relative intensity) 258 (81), 215 (7), 188 (base), 161 (66); HRMS, m/e for C14H14N2O3 calculated 258.100442, found 258.100227; analysis for C14H14N2O3 calculated C, 65.11; H, 5.46; N, 10.85; found C, 65.22; H, 5.51; N 10.01.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5][Cl:6].[BH4-].[Na+].Cl.[O:16]1CCOCC1>O>[OH:16][C:2]1([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][CH:3]1[CH2:4][CH2:5][Cl:6]
Reactant: C1COCCO1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OC1(Cl)C=C(Cl)C=CC1CCCl
Reaction time: 2 h

Procedure:
To a solution of 52 g (0.23 m) of 2,4-dichlorophenacyl chloride in 200 ml of dioxane is added 9 g (0.24 m) of sodium borohydride dissolved in 60 ml of water dropwise at 50°. The addition is set at such a rate that the reaction temperature does not exceed 50°. After the addition, the reaction mixture is stirred at 50° for 11/2 hours. Excess sodium borohydride is carefully decomposed by slow addition of 10% hydrochloric acid. The organic product is extracted into ether and the combined ether extracts are washed with water, saturated sodium bicarbonate solution, and dried over MgSO4. Solvent is evaporated to give 49 g of product.
Reaction SMILES: B(F)(F)F.CCOCC.[Li+].[C-:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[C:21]2([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:20]1>C1COCC1>[OH:19][C:21]1([CH2:20][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: [C-]#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: FB(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(CC#Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Boron trifluoride diethyl etherate (0.131 mL, 1.03 mmol) followed by lithium phenylacetylide (1M in THF, 1.03 mL, 1.03 mmol) was dropped into a solution of Compound 256a (200 mg, 0.938 mmol) in THF (5 mL) stirred at −75° C. under nitrogen atmosphere. Stirring and cooling were kept on for 2 h and after overnight stirring at r.t., the reaction mixture was quenched with water and EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (EtOAc—Petroleum Ether 85:15) affording the title product (272 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15]OS(C)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[N:24](S(C)(=O)=O)[N:23]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([NH2:39])=[O:38].CCN(CC)CC>CC#N>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][N:32]3[CH2:36][CH2:35][CH2:34][CH:33]3[C:37]([NH2:39])=[O:38])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:6]=1)([CH3:2])[CH3:3]
Reactant: NC(=O)C1CCCN1
Reactant: Cc1cc(Nc2cc3cc(COS(C)(=O)=O)ccc3c(OC(C)C)n2)nn1S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Nc2cc3cc(CN4CCCC4C(N)=O)ccc3c(OC(C)C)n2)n[nH]1
Reaction time: 8 h

Procedure:
A mixture of 50 mg methanesulfonic acid 1-isopropoxy-3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ylmethyl ester, 50 mg pyrrolidine-2-carboxylic acid amide and 54 mg Et3N in 10 mL CH3CN was stirred at r.t overnight. After removal of solvent, the residue in MeOH was sent to prep-HPLC to give 1-[1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ylmethyl]-pyrrolidine-2-carboxylic acid amide as a yellow solid. LC-MS m/e 409 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([CH3:37])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2].Br[CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:52])[CH:48]=2)[N:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([CH3:37])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:13][C:12]([O:21][CH2:41][C:42]1[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[C:47]([F:52])[CH:48]=3)[N:43]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Reactant: Fc1ccc2nc(CBr)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To 3-{3-tert-Butylsulfanyl-5-hydroxy-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (D-2; 6.5 g, 11.9 mmol) in MeCN (75 mL) was added 2-bromomethyl-6-fluoro-quinoline (3.14 g, 13.1 mmol), and Cs2CO3 (9.7 g, 29.8 mmol). The reaction was stirred at room temperature overnight, after which LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (D-3, 7.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:30])[C@@H:12]([NH:22]C(OC(C)(C)C)=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:30])[C@@H:12]([NH2:22])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2C#N)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
2-[(S)-2-tert-Butoxycarbonylamino-3-(2-cyano-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (3.2 g, 7.4 mmol) was dissolved into dry dichloromethane (20 mL) and trifluoroacetic acid (25 mL, 325 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was cooled in an ice bath, then neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give crude 2-[(S)-2-amino-3-(2-cyano-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester as a pale yellow solid (2.1 g, 86%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][NH:11][C:12]1[NH:20][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:17]2[CH:18]=[CH:19][C:14]3=[N:13][C:12]([NH:11][CH3:10])=[N:20][C:15]3=[CH:16]2)=[CH:4][CH:5]=1
Reactant: CNc1nc2ccncc2[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc2ccn(Cc3ccc(F)cc3)cc-2n1
Temperature: 60 °C

Procedure:
A mixture of 5.6 parts of 1-(chloromethyl)-4-fluorobenzene, 5.2 parts of N-methyl-3H-imidazo[4,5-c]pyridine-2-amine, 4.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated first for 3 hours at 90°-100° C. and further overnight at 60° C. The reaction mixture was poured onto water and the product was extracted four times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 2-propanone, yielding 6 parts of 5-[(4-fluorophenyl)methyl]-N-methyl-5H-imidazo[4,5-c]pyridin-2-amine; mp. 209.5° C. (intermediate 97).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C@H:12]([CH2:17][OH:18])[CH2:11]2)([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C@H:12]([CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH2:11]2)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@H](CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61.6 %

Procedure:
The aforementioned (S)-2-hydroxymethyl-indan-5-yl-carbamic acid tert-butyl ester (2.15 g, 8.16 mmol) was dissolved in 50 mL of CH2Cl2. p-Toluenesulfonyl chloride (1.63 g, 8.54 mmol) and DMAP (1.1 g, 9.0 mmol) were added and the solution was stirred for 22 hours at rt. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed in turn with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and brine (100 mL each). Each wash was extracted with a small portion of CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and evaporated. The residue was dissolved in warm ethyl ether (25 mL) and allowed to crystallize. The solid was filtered, washed with cold ethyl ether and dried to provide a beige solid as toluene-4-sulfonic acid (S)-5-tert-butoxycarbonylamino-indan-2-ylmethyl ester (2.1 g, 86%). 1H-NMR and MS data were compatible with the structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.[Cl:16]([O-])=O.[Na+]>C(O)C>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[CH2:10]2
Reactant: CC(=O)Nc1cccc2c1CN(C)C2
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(Cl)c2c1CN(C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(2,3-dihydro-2-methyl-1H-isoindol-4-yl)acetamide (20 g), hydrochloric acid (37%, 2.5 mL), and sodium chlorite (15%, 10 ml) in 96% ethanol (20 mL) was stirred at room temperature for 4 hours. The solvent was removed by evaporation, whereafter the residue was treated with saturated Na2CO3 in water to pH=7. The precipitated product was filtered off and washed with water and ether. Yield 1.1 g, mp 147-150° C.
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:28]([N:30]=C=S)[CH3:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:28]([NH:30][C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2)[CH3:29]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: CCN=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH2Cl2 (2 mL), ethyl isothiocyanate (0.042 ml, 0.48 mmol), EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 ml, 1.49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80° C. and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36% yield).