Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)C=CC=CC=1.BrCCCCCCCCCO.[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O(CCCCCCCCC(O)=O)C1C=CC=CC=1.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH2:71])[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH:71][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: OCCCCCCCCCOc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccccc1
Agent: OCCCCCCCCCBr
Solvent: Oc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccccc1

Procedure:
The title compound, m/e=379.4 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, phenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-phenoxy-nonan-1-ol, which was oxidized in step 2 to 9-phenoxy-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-phenoxy-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14](=[O:16])[CH3:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Reaction time: 3 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 1H-indol-3-yl acetate (8 g, 45.69 mmol) in tetrahydrofuran (150 mL). To this was added acetic anhydride (46.6 g, 456.86 mmol). Addition of triethylamine (9.25 g, 91.49 mmol) was next. To the mixture was added DMAP (1.11 g, 9.10 mmol). The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 300 mL of ethyl acetate The resulting mixture was washed 2 times with 150 mL of NaCl(aq.). The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 20:1 petroleum ether/ethyl acetate solvent system. This resulted in 6.6 g (67%) of 1-acetyl-1H-indol-3-yl acetate as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 58.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.80 g, 30.0 mmol), 3-fluoro-4-methoxybenzaldehyde (4.86 g, 1.05 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (5.2 g, 59%) as white crystals. MP: 68° C.
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][C:11]([Cl:17])=[C:10]([CH3:18])[C:9]=1[Br:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>O.C1(C)C=CC=CC=1.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>[Br:19][C:9]1[C:8]([C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=2)=[C:13]([C:14](=[O:16])[CH3:15])[CH:12]=[C:11]([Cl:17])[C:10]=1[CH3:18]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
To a solution of sodium hydrogenecarbonate (2.8 g, 34 mmol) in water (70 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (6.7 g, 17 mmol) in toluene (70 mL) followed by (3,5-difluorophenyl)boronic acid (2.9 g, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.98 g, 0.85 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered, concentrated and purified on silica gel (eluting with 0-15% of ethyl acetate in hexanes) to give the desired product (5.6 g). LCMS calculated for C15H11BrClF2O (M+H)+: m/z=359.0. found: 359.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].I([O-])(=O)(=O)=[O:16].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:16])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of N-(2-Fluoro-4-vinylphenyl)methansulfonamide (20-2, 1.076 g, 5 mmol) in acetone and water (1:1, 20 mL) was treated with a catalytic amount of osmium tetroxide (4 wt % solution in hydroxyperoxide) and sodium periodate (2.139 g, 10 mmol). After being stirred at room temperature for 1 h, the mixture was concentrated into a small volume in vacuo. The residue was treated with aqueous sodium thiosulfate solution and then extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant to afford N-(2-Fluoro-4-formylphenyl)methanesulfonamide (20-3, LJO-326, 0.521 g, 48%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C)=[CH:5][N:4]=1.IC1C=CC=CC=1[F:27]>>[F:27][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]#[C:11][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: Fc1ccccc1I
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Product: COc1cc(C#Cc2ccccc2F)cnc1OC

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-2-fluorobenzene instead of 1-iodo-2-methylbenzene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[N:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[N:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 86-7 (241 mg, 1.3 mmol), 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (224 mg, 1.3 mmol), 1,3-dicyclohexylcarbodiimide (325 mg, 1.6 mmol) and 4-(dimethylamino)pyridine (26 mg, 0.26 mmol) in DMF (6 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered to remove the solid and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 145-4 as pale yellow solid. MS m/z 340.2 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:31]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:32])[CH:38]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 31.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.5 g, 3.8 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (1.07 g, 4.57 mmol), potassium carbonate (1.74 g, 12.6 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.027 g, 0.038 mmol), DME (13 mL), and water (7 mL) was stirred in a pressure vessel. The vessel was sealed, and the suspension was heated at 110° C. for 22 hours and allowed to cool to room temperature. The DME was removed under reduced pressure, and the resulting mixture was extracted with dichloromethane (3×25 mL) and ethyl acetate (25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting tan solid (2.11 g) was dissolved in dichloromethane (15 mL), purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate). The resulting foamy solid was concentrated twice from methyl acetate, and the resulting solid was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 601 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(morpholin-4-ylcarbonyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a white solid, mp 149-152° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[ClH:16].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CC2CCN(CCOc3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (600 mg, 2.66 mmol), 2-(4-chlorophenoxy)ethyl bromide (658 mg, 2.79 mmol) and K2CO3 (754 mg, 5.45 mmol) in CH3CN (50 mL) as colorless flakes (661 mg): mp 201-203° C.; 1H NMR (CDCl3) 1.60-2.12 (m, 5H), 2.31 (s, 3H), 2.58 (d, J=7.2 Hz, 2H), 2.63-2.82 (m, 2H), 3.20-3.50 (m, 2H), 3.58-3.70 (m, 2H), 4.53 (t, J=4.2 Hz, 2H), 6.80 (d, J=9.3 Hz, 2H), 7.00 (d, J=7.5 Hz, 2H), 7.09 (d, J=7.8 Hz, 2H), 7.24 (d, J=8.7 Hz, 2H), 12.60 (b, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:20]=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17]>C(#N)C>[N+:16]([C:19]1[CH:20]=[N:21][N:22]([CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])[CH:23]=1)([O-:18])=[O:17]
Reactant: O=C1CCCN1CCCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCN1CCn1cc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
1-(2-Chloroethyl)pyrrolidin-2-one (0.72 g, 4.8 mmol) was added to a solution of potassium carbonate (1.2 g, 8.7 mmol), 4-nitro-1H-pyrazole (0.5 g, 4.4 mmol) in dry acetonitrile (4 mL) and the reaction was stirred at 60° C. overnight. The solvent was concentrated in vacuo, then the residue was slurried in water, collected by filtration and dried in vacuo to afford 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrrolidin-2-one (0.21 g, 0.9 mmol). LC-MS (Method H), RT=1.23 min. (ES+) 225.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:29]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1ccoc1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccoc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-furanboronic acid in General Procedure A. Purification on silica yielded 231. NMR (CDCl3): 2.66-2.68 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.28-3.31 (m, 4H, 2×CH2), 3.86-3.88 (m, 6H, 3×CH2), 3.98-4.01 (m, 4H, 2×CH2), 7.04 (d, H, ArH, J=1.65 Hz), 7.26 (ms, H, ArH-part under CDCl3), 7.46 (ms, H, ArH), 8.18 (s, H, ArH). MS: (ESI+): MH+ 464.16
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12].N1C=CC=CC=1>C(OCC)(=O)C>[C:5]([NH:12][C:11]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:9]([Cl:8])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C)c(Cl)c1
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
Acetic anhydride (78 ml, 0.825 mol) was added in portions (using a dropping funnel) during a 45 min period to a stirred, cooled in an ice-bath solution of 3-chloro-4-methylaniline (106.2 g, 0.75 mol) in ethyl acetate (550 ml, dried over MgSO4 prior to use) and anhydrous pyridine (66.6 ml, 0.825 mol) under argon. During the reaction the temperature of the reaction mixture varied between 10-20° C. Stirring was continued for 20 min; then the ice-water bath was removed and the reaction mixture was stirred for 18 h at room temperature. The solvents were removed in vacuo and the light brown solid residue was triturated with ether (350 ml) and left to stand in a fridge overnight. The solid was collected by filtration, washed with cold ether (100 ml) and hexanes (100 mL), dried over P2O5 to afford a white solid (90 g). The filtrate was concentrated in vacuo, triturated with ether to afford an additional 28.1 g of the product. Total yield 118.1 g (86%); mp 105-106° C.; 1H-NMR (CDCl3) 2.17, 2.32 (2×s, 6H, 4-CH3, CH3CO), 7.14 (d, J=8.22 Hz, 1H, 6-H), 7.25 (2×dd, J=1.9, 6.5 Hz, 1H, 5-H), 7.58 (d, J=1.8 Hz, 1H, 3-H); MS (FAB, m/z) 184, 186 [(M+H)+ 100%, 30% respectively; Cl isotopic pattern].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]#[N:19])[CH:7]=1.O.O.[Sn](Cl)[Cl:26].Cl>CCO>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]=[C:18]([NH2:19])[C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Combine 2-(5-fluoro-2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (2.15 g, 6.87 mmol) and Tin(II) chloride, dihydrate (4.65 g, 20.6 mmol) in a mixed solvent of EtOH (25 mL) and 5.0 N HCl (25 mL), heat the suspension to reflux for 3 hours, cool to RT. Suction filtration obtains the title compound 1.73 g (yield 78%) as a yellow solid by. Mass spectrum: ACPI (m/e): 284((M+1-HCl); 1H NMR (300 MHz, DMSO-d6) δ 11.46 (br, 1H), 10.02 (br, 1H), 9.02 (br, 2H), 7.90-7.87 (m, 1H), 7.71-7.68 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.28 (m, 1H), 7.12-6.94 (m, 2H), 6.85-6.81(m, 1H).
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH2:21][C:22]([CH3:25])([CH3:24])[N:23]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH3:11])[C:7]=2[CH:12]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(#N)C>[CH3:24][C:22]1([CH3:25])[CH2:21][O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[C:3]3[CH:4]=[CH:5][C:6]4[N:10]=[N:9][N:8]([CH3:11])[C:7]=4[CH:12]=3)=[CH:14][CH:15]=2)=[N:23]1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(C4=NC(C)(C)CO4)cc3)cc21
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Cn1nnc2ccc(C(c3ccc(C4=NC(C)(C)CO4)cc3)n3ccnc3)cc21
Yield: 65.6 %

Procedure:
A solution of 10 parts of 6-[chloro[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]methyl]-1-methyl-1H-benzotriazole and 10 parts of 1H-imidazole in 80 parts of acetonitrile was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the product was extracted with ethyl acetate. The extract was washed with a diluted potassium carbonate solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7.1 parts (65.6%) of 6-[[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl](1H-imidazol-1-yl)methyl]-1-methyl-1H-benzotriazole as a residue (int. 231).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([O:11][CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C1CCC(O)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(tert-butyl)cyclohexan-1-ol (500 mg, 3 mmol) was dissolved in pyridine (50 mL) and stirred at room temperature for 30 min. Tosyl chloride (915 mg, 4.79 mmol) was added to the reaction mixture and allowed to stir overnight. The reaction was quenched by addition of water (50 mL) and extracted with ether. (3×20 mL) washed with saturated CuSO4, water, saturated aqueous NaHCO3, water, and dried, (Na2SO4) concentrated and purified (10% EtOAc in hexane) to give 38 as a white solid.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:34][C:33]([F:36])([F:35])[C:29]1[N:30]=[C:31]([N:10]2[CH2:11][CH2:12][CH:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]3)[CH2:8][CH2:9]2)[CH:32]=[CH:27][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: FC(F)(F)c1nccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccnc(C(F)(F)F)n3)CC2)CC1
Temperature: 70 °C

Procedure:
The tert-butyl 4,4′-bipiperidine-1-carboxylate (28.5 mg, 0.11 mmol) and cesium carbonate (106 mg, 0.32 mmol) were stirred in NMP (0.5 ml) and the 4-bromo-2-(trifluoromethyl)pyrimidine (12 mg, 0.053 mmol) was added. The mixture was heated at 70° C. for 2 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20].COC(=O)C1C=CC(Cl)=NC=1NC1C=CC(Br)=CC=1F.C[O-].[Na+].CO>C(O)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[NH:6][C:7](=[O:10])[CH:8]=[CH:9][C:4]=2[C:3]([OH:21])=[O:2])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Agent: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-methoxynicotinic acid methyl ester: To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid methyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9 mmol) was added MeOH (50 mL) to give a slurry that was stirred at 60-65° C. for 16 hours under N2. Additional sodium methoxide (0.791 g, 13.9 mmol) was added and the reaction mixture was allowed to stir another 3 days at 60-65° C. The reaction mixture was cooled to room temperature and glacial acetic acid was added dropwise until the pH was 7. The resulting suspension was filtered and washed with H2O to yield a pink solid that was collected and dried under vacuum to yield 1.74 g (88%) pure desired product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][CH:11]=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:25]=[O:26])C>>[N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][C:11]([CH:25]=[O:26])=[CH:10][C:9]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2c([nH]1)CCCC2CCN1CCCC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
4-(2-Pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole (475 mg, 2.2 mmol) was formylated with POCl3 (0.25 mL, 1.2 eq.) and DMF (2 ml) using standard Vilsmierer condition to give 250 mg of 4-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as alight yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Product: Cn1ncc([N+](=O)[O-])c1N1CCOC(CNC(=O)OC(C)(C)C)C1
Yield: 93 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl morpholin-2-ylmethylcarbamate gave tert-butyl (4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholin-2-yl)methylcarbamate as a yellow oil (196 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 4.92 (s br, 1H), 4.00 (dd, J=11.3, 2.9 Hz, 1H), 3.90-3.68 (m, 5H), 3.57 (td, J=11.6, 3.2 Hz, 1H), 3.38-3.24 (m, 2H), 3.15 (ddd, J=14.1, 7.1, 5.1 Hz, 1H), 2.86 (d, J=11.8 Hz, 1H), 2.77 (d, J=11.8 Hz, 1H), 1.45 (s, 9H)