Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH3:22])=[C:20]([CH3:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][C:19]=1[CH3:22]
Reactant: C#CCCn1nc2ccc(C)c(C)c2n1
Reactant: Brc1ccccn1
Product: Cc1ccc2nn(CCC#Cc3ccccn3)nc2c1C
Yield: 60.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 65 mg (0.23 mmol, 63%) of 4,5-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][C:50]([Si:53]([CH3:64])([CH3:63])[O:54][C:55]1[CH:56]=[C:57]([CH2:61][NH2:62])[CH:58]=[CH:59][CH:60]=1)([CH3:52])[CH3:51]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:62][CH2:61][C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([O:54][Si:53]([C:50]([CH3:52])([CH3:51])[CH3:49])([CH3:63])[CH3:64])[CH:56]=2)=[O:7])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: Cc1cc(C(=O)O)cc(Cl)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A suspension of 3-chloro-4-hydroxy-5-methylbenzoic acid (4.7 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. and BOP reagent (12.3 g, 27.8 mmol) was added, followed by diisopropylethylamine (13.2 mL, 75.6 mmol). A solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanamine (Example 8; 6.59 g, 27.8 mmol) in dry dichloromethane (10 mL) was added by syringe and the resulting solution was stirred at 0° C. for 3 h. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (2×50 mL), aqueous sodium hydrogen carbonate (100 mL), brine (100 mL), and water (100 mL)dried (MgSO4), filtered, evaporated, and chromatographed (30% ethyl acetate/hexanes) to give 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenol (6.03 g, 59%) as a pale pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CN(C)C=O>CO>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:11]/[C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Yield: 82.6 %

Procedure:
A 12-l. three-necked flask, equipped with a thermometer, a mechanical stirrer and a 60 cm. vacuum-jacketed silvered column with glass helice packing connected to a total-condensation, variable take-off still head with receiver was charged under nitrogen with 675 g (4.46 moles) of 2-nitro-1,4-dimethylbenzene, 736 g (6.17 moles) of N,N-dimethyl formamide dimethyl acetal and 3.0 l of N,N-dimethylformamide. The mixture was stirred and heated with a heating mantle for 37 hours. The pot temperature was gradually raised from 130° to 144° while the formed methanol was removed by distillation. The fractionating column was replaced by a distilling head with condenser and receiver (cooled in a dry ice-acetone bath). The dimethylformamide was removed by distillation, first at aspirator vacuum and then at high vacuum (water bath 70°), giving a residue of 924 g (100%) of crude product as a dark red viscous oil. This material was poured into a beaker and mixed thoroughly with 640 ml of methyl alcohol. The mixture was stirred in an ice bath until the product crystallized in mass and was then refrigerated overnight. The precipitate was collected by suction filtration, washed with 320 ml of methyl alcohol and dried in vacuo at room temperature (constant weight) to afford 760 g (83%) of product as a free-flowing, dark-red crystalline solid, m.p. 41.5-43.5° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>CS(C)=O.C(OCC)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:22][CH2:21]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CNCC1CCc2cccc(-c3ccccc3Cl)c2O1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
To a suspension of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.30 mmol) in dimethylsulfoxide (0.5 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 1.5 mL, 3.0 mmol) and the mixture heated to 60° C. in a sealed vial for 24 hours. The cooled reaction mixture was then diluted with diethyl ether (10 mL), washed with water (5×5 mL) and saturated brine (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave 69 mg (79%) of N-{[8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}-N-methylamine. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (3 drops). The resulting white precipitate was filtered to afford 74 mg (76%) of N-{[8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}-N-methylamine hydrochloride as a white solid. HRMS: calcd for C17H18ClNO+H+, 288.11497. found (ESI, [M+H]+), 288.1143.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[C:12]([NH:4][CH2:3][CH2:1][OH:2])(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of ethanolamine (3.42 ml, 56.6 mmol) and triethylamine (5.51 ml, 39.5 mmol) in dry tetrahydrofuran (150 ml) was cooled in ice bath and decanoyl chloride (5.44 ml, 26.3 mmol) in tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight and filtered. The filtered solution was concentrated in vacuo. The residue was diluted with ethyl acetate (300 ml) and washed with 0.1% HCl (50 ml×3), saturated NaHCO3 (50 ml×3), brine (50 ml), and water (50 ml). The organic solution was dried over MgSO4 and solvent was removed on a rotovap. The crude product was purified by flash column chromatography, eluting with a gradient of dichloromethane/methanol (95:5) to dichloromethane/methanol (9:1) to give 5.57 g of a white solid NAE-10:0 (99% yield): Rf=0.35 in dichloromethane/methanol (95:5); 1H NMR (CDCl3) 6 6.11 (br, 1H), 3.72 (m, 2H), 3.42 (m, 2H), 3.08 (br, 1H), 2.20 (t, J=7.9 Hz, 2H), 1.64 (m, 2H), 1.26–1.29 (m, 12H), 0.88 (t, J=6.8 Hz, 3H); FT-IR (Table 1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](C)[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:18][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(C)c(I)c1
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C2C3=C(COCC3=O)NC3=C2C(=O)OC3)cc1I
Temperature: -10 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
The product from Example 5A (0.60 g, 1.4 mmol) in chloroform (10 mL) under a nitrogen atmosphere was treated with pyridine (0.13 mL, 1.6 mmol) and pyridinium tribromide (0.48 g, 1.5 mmol) at −10° C. After stirring at −10° C. for 2 hours, the mixture was allowed to warm to ambient temperature and then was treated with 1M HCl and extracted with chloroform. The chloroform layer was dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 1 hour and cooled to ambient temperature. Purification of the residue by chromatography on silica gel eluting with 10% methanol in dichloromethane provided the title compound (0.28 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12](I)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C([Mg]Br)C.[CH3:20][CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:22]([CH2:23][CH3:24])([OH:25])[CH2:21][CH3:20])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCC(=O)CC
Reactant: CCOC(=O)c1cc2ccc(I)cc2s1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(O)(CC)CC)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a stirred solution of 6-iodo-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.95 g, 8.88 mmol) in THF (60 mL) at −78° C. is added ethylmagnesium bromide (4.45 mL, 3.0 M). The reaction mixture is stirred for 15 min, and 3-pentanone (3.0 mL) is added. The mixture is allowed to warm to RT and stirred for 30 min. The reaction is quenched with HCl (15 mL, 1.0 M) and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give the title compound (0.65 g, 25%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#C[Si](C)(C)C)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=272.3 (M++H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and trimethylsilylacetylene.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27]2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=[C:23]([NH2:30])[C:22]=2[N:21]=[C:20]1[CH3:31]>>[NH2:30][C:23]1[C:22]2[N:21]=[C:20]([CH3:31])[N:19]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:27]=2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 17–32, trans-2-phenylcyclopropylcarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method B. The observed accurate mass was 408.2392.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15](I)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH:43][CH:44]3[CH2:49][CH2:48][CH2:47][N:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45]3)[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:37]3[CH:38]=[C:39]([NH:43][CH:44]4[CH2:49][CH2:48][CH2:47][N:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45]4)[CH:40]=[N:41][CH:42]=3)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(B3OC(C)(C)C(C)(C)O3)c2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC4CCCN(C(=O)OC(C)(C)C)C4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A suspension of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (73 mg, 0.143 mmol) and crude tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ylamino)piperidine-1-carboxylate (113 mg, 0.279 mmol) in toluene (1.000 mL) and EtOH (1 mL) was treated with Na2CO3, 2.0 M (0.143 mL, 0.286 mmol) and Pd(PPh3)4 (16.53 mg, 0.014 mmol, Strem). The reaction mixture was degassed, backfilled with argon and heated to 100° C. under N2. After 15 h, the reaction was cooled to 23° C., filtered through celite, and purified by silica gel chromatography (eluent: 0.5-10% MeOH/DCM), affording tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (Rf=0.5 in 10% MeOH/DCM, desired product) (33 mg, 35%); along with a byproduct, tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (Rf=0.2 in 10% MeOH/DCM, de-tosylated product) (31 mg, 43%). MS (ESI, pos. ion) m/z: 660.3 (M+1)
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=2[O:28][CH3:29])=[C:5]([CH3:30])[N:4]=1.[C:31]([O-])(O)=O.[Na+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:31])=[O:26])=[CH:20][C:19]=2[O:28][CH3:29])=[C:5]([CH3:30])[N:4]=1
Reactant: O=C([O-])O
Reactant: CCCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a stirred solution of the product from step (i) (0.1 g) in MeOH (2 mL) and the mixture was heated at 70° C. for 2 h. The mixture was allowed to cool and then poured into saturated aqueous NaHCO3 solution (5 mL). The mixture was adjusted to pH ˜7 by adding NaHCO3 and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.014 g.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([NH:9][CH3:10])[C:5]([NH2:8])=[CH:6][CH:7]=1.[NH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]([C:20](O)=O)[CH3:19].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:26]([O:25][C:23](=[O:24])[NH:17][C@H:18]([C:20]1[N:9]([CH3:10])[C:4]2[C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:19])([CH3:29])([CH3:28])[CH3:27]
Reactant: CNc1c(N)ccc(F)c1-c1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A solution of 4-fluoro-N2-methyl-3-pyridin-2-yl-benzene-1,2-diamine (0.75 g, 3.44 mmol), Boc-Ala (0.72 g, 3.78 mmol), HOAt (0.52 g, 3.78 mmol) in DCM (10 mL) was cooled to 0° C. EDC (0.73 g, 3.78 mmol) was added portion wise and the resulting mixture was stirred for 1 h. The mixture was diluted with DCM (20 mL) and the organic layer was washed with citric acid, brine, dried (MgSO4) and evaporated. The resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a white solid (0.3 g, 24%). LCMS (Method J): RT 2.42 min [M+H]+ 371
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O1CCCC1>[N:6]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Bromoacetic acid (2 g, 14.4 mole) was dissolved in tetrahydrofuran (50 mL) and added dropwise to a stirred solution of morpholine (3.76 g, 43.2 mole) in tetrahydrofuran (THF, 20 mL). The solution was stirred at room temperature for three days. The white solid (4.17 g) was filtered, washed with THF (100 mL), and recrystallised from hot ethanol (EtOH), Yield: 2.59 g: IR:1740 cm-1. For the two different isobaric versions of morpholine acetic acid, either bromoacetic-1-13C acid (Aldrich PN 27,933-1) or bromoacetic-2-13C acid (Aldrich PN 27,935-8) was substituted for bromoacetic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[C:26](#[N:28])[CH3:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:6]([CH3:9])=[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[N:4]=[N:3][C:2]=1[CH2:27][C:26]#[N:28]
Reactant: CC#N
Reactant: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: Cc1c(CC#N)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
3-Chloro-4,5-dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazine (1.0 g, 2.64 mmol), acetonitrile (0.225 mL, 4.22 mmol), and toluene (5 mL) are combined and cooled to 0° C. LiHMDS (8.4 mL, 1.0 M, 8.4 mmol) is added dropwise over 5 min. The reaction is stirred at 0° C. for 1 h, then warmed to room temperature and stirred an additional 16 h. The reaction is quenched by the addition of saturated aq. NH4Cl, and the organics are extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel (0-100% EtOAc in heptanes) to afford the title compound as an orange solid (500 mg, 50%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[C:17]([OH:19])=O.[O:20]=[C:21]1[CH:26]([N:27]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:25][CH2:24][C:23](=[O:43])[NH:22]1>>[O:20]=[C:21]1[CH:26]([N:27]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:11]2=[O:13])[CH2:25][CH2:24][C:23](=[O:43])[NH:22]1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cccc(NCc2cccs2)c1C(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccs4)c3C2=O)C(=O)N1
Yield: 29 %

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-phthalic acid (2.88 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by preparative HPLC (Symmetry C18, isocratic, 35% acetonitrile/water) to give 0.31 g (29%) of product as a yellow solid: mp 223-225° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.39 (d, J=4.8 Hz, 1H), 7.23-6.96 (m, 5H), 5.07 (dd, J=5.3 and 12.4 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.46 (m, 2H), 2.09-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 170.03, 168.67, 167.20, 145.60, 142.51, 136.04, 132.15, 126.88, 125.40, 125.00, 117.67, 111.05, 109.80, 48.56, 40.88, 30.96, 22.10; Anal. Calcd. For C18H15N3O4S: C, 58.53; H, 4.09; N, 11.38. Found: C, 58.20; H, 3.96; N, 10.99.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[CH:5]=[N:6][OH:7].[CH2:13]=[CH2:14].[O-]Cl.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:5]2[CH2:14][CH2:13][O:7][N:6]=2)[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1c(Cl)ccc(Cl)c1C=NO
Reactant: C=C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1c(Cl)ccc(Cl)c1C1=NOCC1
Reaction time: 8 h

Procedure:
In a pressure container, 50 g (0.25 mol) of 3,6-dichloro-2-methylbenzaldoxime are dissolved in 750 ml of methylene chloride. 16 g of ethylene are applied, and 620 g of a 12.5% strength solution of NaOCl are then pumped in at room temperature, and the mixture is stirred overnight. The pressure vessel is vented, and the organic phase is then separated off, washed once with water and dried, and the solvent is removed under reduced pressure. This gives 58 g of product (95% pure) (95% of theory). 1H-NMR (DMSO-D6): 2.3 ppm (s, 3H, Me), 3.3 ppm (t, 2H, CH2), 4.5 ppm (t, 2H, CH2), 7.45 ppm (d, 1H, arom-H), 7.6 ppm (d, 1H, arom-H).
Reaction SMILES: C(OC(=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)[CH3:8])(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:26]1[N:25]=[CH:24][C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:8])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(F)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3ccc(F)nc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(6-fluoro-pyridin-3-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(6-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 57%.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][CH:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[Li].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: [Li]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a stirred solution of 4-bromobenzoyl chloride (20.0 g, 91.1 mmol) in dichloromethane (300 mL) at −78° C. was added triethylamine (28.0 mL, 200.0 mmol), and O,N-dimethylhydroxylamine hydrochloride (9.33 g, 95.6 mmol). The resulting solution was allowed to warm to room temperature, stirred for 1.5 hours, and then concentrated. The residue was triturated in acetone and the resulting solid was dissolved in ethyl acetate washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-bromo-N-methoxy-N-methylbenzamide (18.6 g, 84%). To a solution of 4-bromo-N-methoxy-N-methylbenzamide (3.0 g, 12.29 mmol) in THF (30 mL) at 0° C. under nitrogen was added 2-thienyllithium (1.0 M in THF, 15 mL, 15 mmol) slowly over 10 minutes. The solution was stirred at 0° C. for 1 hour, poured into a saturated aqueous ammonium chloride solution (150 mL), and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ether to give (4-bromophenyl)(thien-2-yl)methanone as a brown solid (1.1 g, 34%). MS (ES) m/z 266.9.