Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH:7]([NH2:10])([CH3:9])[CH3:8]>C(Cl)Cl>[CH:7]([NH:10][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])([CH3:9])[CH3:8]
Reactant: CC(C)N
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: CC(C)NC(=O)C(Cl)Cl
Temperature: 0 °C
Yield: 98 %

Procedure:
Dichloroacetyl chloride, 442.5 grams (3.0 mole), was dissolved in a flask containing 900 milliliters of methylene chloride and the solution cooled to 0° C. in an ice/acetone bath. 354 grams (5.98 mole) of isopropyl amine was added dropwise with vigorous stirring and the addition rate was adjusted to maintain the reaction temperature below 5° C. When the addition was complete, the mixture was allowed to stir at ambient temperature for one hour then washed with 2×500 milliliters water, the organic phase separated, dried over magnesium sulfate and stripped of solvent at reduced pressure giving 499 grams (98% yield) of the desired product, a white solid, m.p. 45°-48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=C[C:8]=2Cl)[CH:6]=1.[Br:15]N1C(=O)CCC1=O.[C:23]([Cl:27])(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][Br:15])=[C:23]([Cl:27])[CH:8]=2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1cnn(-c2ccc(CBr)c(Cl)c2)c1
Yield: 68 %

Procedure:
16 g of 4-chloro-1-(3-chloro-p-tolyl)pyrazole, 13 g of N-bromosuccinimide, 0.32 g of dibenzoylperoxide and 170 ml of carbon tetrachloride are heated to the boil for 1.5 hours. The resulting solution is cooled, filtered and evaporated to dryness. The obtained residue (20.1 g) is recrystallized from cyclohexane to yield 14.7 g (68% of theory) of 4-chloro-1-(4-bromomethyl-3-chlorophenyl)pyrazole (m.p. 77° to 78° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)([O-:3])=[O:2].Br[CH2:17][CH:18](OCC)OCC.C(O)C.CN(C)C(=O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][CH:17]=[CH:18][N:14]=1)=[CH:9]2)([O-:3])=[O:2]
Reactant: NC(=S)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 100 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A mixture of 7-nitro-1H-indole-2-carbothioamide (2.06 g), 2-bromo-1,1-diethoxyethane (3.67 g), ethanol (10 mL) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 4 hr. To the reaction mixture was added water, and the resulting crystals were filtrated, washed with water and hexane, and dried to give the title compound (2.21 g, yield 97%) as yellow crystals. melting point 130-131° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Cl:15][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1
Reactant: OCCN1CCc2sccc2C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCCN1CCc2sccc2C1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.49 g) in dichloromethane (20 ml) was added dropwise thionyl chloride (0.39 ml). The mixture was stirred at 40° C. for 1.5 hours. After the mixture was evaporated under reduced pressure, the residue was triturated with diisopropyl ether. The resulting powder was collected by filtration, washed with diisopropyl ether and dried in vacuo to give 5-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (0.44 g).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH2:18]([NH2:21])[C:19]#[CH:20]>CO>[C:1]([NH:3][C:4]([NH:21][CH2:18][C:19]#[CH:20])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1ccccn1)NC#N
Solvent: CO
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
A mixture of the product of Step A (4.0 g; 15.0 mmoles) and propargylamine (6.88 g; 125 mmoles) in methanol (20 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 20 hours. The reaction mixture was evaporated under reduced pressure and the product recrystallized from acetonitrile to give the title compound; mp 124.5°-130.5° C. (remelted at 128°-131.5° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH:34]=O)[CH:27]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:1][C:2]([CH3:24])([CH3:25])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:15]([CH:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])[NH:14][CH2:34][CH2:33][O:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:6]=1
Reactant: CC1CCC(C(=O)N(N)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Reactant: O=CCOc1cccnc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1CCC(C(=O)N(NCCOc2cccnc2)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1

Procedure:
The title compound was synthesized from 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-hydrazino]-thiophene-2-carboxylic acid and (pyridin-3-yloxy)-acetaldehyde in a manner similar to that of Example 131. MS (m/z): 484.0 [M−H]+; HPLC retention time: 3.44 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=1[C:19]([Cl:21])=[O:20]>>[ClH:21].[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=1[C:19]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:14]=1)=[O:20]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Product: CN1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3F)n2)CC1
Product: Cl
Yield: 82.8 %

Procedure:
Using a method similar to example 160, using 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 150 mg, 0.724 mmol) and 2,4-difluorobenzoyl chloride (133 μL, 1.08 mmol) yields the title compound (230 mg, 83%). Mass spectrum (ion spray): m/z 348.1 (M+1); Analysis calculated for C18H20N3O2ClF2.0.5H2O. Theory: C, 55.03; H, 5.39; N, 10.70. Found: C, 54.88; H, 5.39; N, 10.73. mp=269-271° C.
Reaction SMILES: [O-][CH2:2]C.[Na+].C(O)C.[C:8]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([CH3:42])([CH3:41])[C:37]([O:39][CH3:40])=[O:38]>C(O)C>[C:8]([NH:16][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([CH3:42])([CH3:41])[C:37]([O:39][CH2:40][CH3:2])=[O:38])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(NC(=O)c1ccccc1)C(=O)OCC
Reactant: CC[O-]
Reactant: COC(=O)C(C)(C)OCCCCCCBr
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)OCCCCCCC(NC(=O)c1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To 5 ml of dry ethanol, 675 mg of 20% sodium ethoxide-ethanol solution and 698 mg of diethyl benzoylaminomalonate were added, and stirred for 30 minutes at room temperature. Then, a solution of 914 mg of methyl 6-bromohexyloxy-2-methylpropionate/4 ml of dry ethanol was added dropwise, and stirred for 15 hours at 50–60° C. The reaction solution was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=5:1) to provide 642 mg of the objective compound as yellowish oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:27]([Mg]Br)=[CH:28][CH3:29].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14](=[O:15])[CH:27]=[CH:28][CH3:29])[CH2:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (1.00 g) in tetrahydrofuran (10 mL) was added 1-propenylmagnesium bromide (0.5M tetrahydrofuran solution, 17.2 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was poured into a mixture of concentrated hydrochloric acid (5 mL) and ice (100 g), and the mixture was stirred for 15 min. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (632 mg, yield 61%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 363 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].C(OC([N:14]([CH:22]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)(C)(C)C.C1C[O:35][CH2:34]C1>>[C:18]([O:17][C:15]([NH:14][C:22]([C:24]1[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=1)([CH3:23])[C:34]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:35])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: CC(c1cc(F)cc(F)c1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Product: CC(C)(C)OC(=O)NC(C)(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of potassium tert-butoxide in THF (300 mL) at −78° C. was added a solution of di-tert-butyl[1-(3,5-difluorophenyl)ethyl]imidodicarbonate from Step A (22.0 g, 61.6 mmol) in THF (200 mL), dropwise, over 45 min. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for 3 h. The reaction mixture was cooled to −78° C. and quenched with 1 N aqueous HCl (300 mL), warmed to 0° C., and poured into Et2O (300 mL). The organic layer was extracted and the aqueous layer was extracted further with Et2O (300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—95:5 to 80:20, to give the title compound. MS: m/z=421 (M+Na+CH3CN).
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:37]>>[ClH:37].[ClH:37].[C:1]1([C:7]2[C:8]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
tert-Butyl 4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazine-1-carboxylate (0.40 g, 1.06 mmol) was placed in DCM (10 mL). TFA (2 mL) was then added, and the reaction was stirred for 1 hour. The reaction was concentrated to dryness, redissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid was collected by filtration, washed with ether, and dried to give 5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.350 g, 94.3% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:45][CH:46]([CH3:48])[CH3:47])[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:45][CH:46]([CH3:48])[CH3:47])[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A glass microwave reaction vessel was charged with N-isopropyl-5-(3-(2-(isopropylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (100 mg, 0.150 mmol) and NaOH (0.3 mL, 3.00 mmol) in p-dioxane (1.0 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with CHCl3/iPrOH (4:1) and washed with water. The organic layer was dried, filtered and concentrated to give the crude N-isopropyl-5-(3-(2-(isopropylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (70 mg, 0.136 mmol, 91% yield), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 514.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(#N)C.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.[Cu]I>[OH:29][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(0) (0.1 g), triethylamine (1.27 g), and CuI (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[NH2:5].N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>CC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CS(=O)(=O)CCc1ccc(N)cc1F
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a stirred solution of 3-fluoro-4-(2-(methylsulfonyl)ethyl)aniline (200 mg, 0.92 mmol) in acetone/DMF (3 mL+1.27 mL), pyridine (0.222 mL, 2.76 mmol) was added dropwise phenyl chloroformate (0.152 mL, 1.197 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. The acetone was evaporated and the residue was diluted with DCM (30 mL). The mixture was washed with saturated NaHCO3 solution (15 mL) and the organic layer extracted with DCM (2×20 mL). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give pure phenyl 3-fluoro-4-(2-(methylsulfonyl)ethyl)phenylcarbamate (260 mg, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=3)[S:29][C:20]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:32][CH:31]=3)[S:29][C:20]=12
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCN(C)CC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
N-methylpiperazine (177 μL, 1.6 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (560 mg, 1.23 mmol) in 12 mL of dichloromethane and 3 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (1.3 g, 6.13 mmol) is added. After stirring at 0° C. for 10 minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 5.5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 215 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 226–228° C.; 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37 (br s, 8H), 3.49 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.40 (d, J=8 Hz, 2H), (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[O:14][C:15](=[O:17])[CH3:16].Cl.[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH2:5][CH:6]([O:14][C:15](=[O:17])[CH3:16])[CH2:7]2)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC1Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)OC1Cc2ccc(C(C)=O)cc2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a mixture at 5-10° C. of aluminum chloride (AlCl3; 30.6 g, 0.229 mol) in carbon disulfide (CS2; 160 mL) was added acetyl chloride (12 mL, 13.2 g, 0.169 mol). To this mixture was added a solution of acetic acid indan-2-yl ester (19.9 g, 0.113 mol, prepared according to the method described in Can. J. Chem. 1967, 45, 1185) in acetyl chloride (12 mL) keeping the temperature below 11° C. The contents were stirred at 5° C. for 3 h and were then carefully added to ice-water (350 mL) containing concentrated HCl (60 mL). The mixture was extracted with CH2Cl2 (2×), and the combined extracts were washed with H2O and were dried over Na2SO4. Concentration gave the title compound (23.8 g, 97%) as a solid: 1H NMR δ 7.84 (s, 1H), 7.82 (m, 1H), 7.32 (d, J=7.0 Hz, 1H), 5.55 (m, 1H), 3.40-3.32 (m, 2H), 3.10-3.05 (m, 2H), 2.60 (s, 3H), 2.04 (s, 3H); EIMS m/z 158 ([M-AcOH]+, 42), 143 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][S:24][CH2:25][CH2:26][NH2:27].Cl>>[ClH:1].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: NCCSCc1nccs1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Agent: Cl
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1ccc(Cl)cc1

Procedure:
An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.36 g) and 2-(2-thiazolylmethylthio)ethylamine (0.9 g) was heated at 130°-135° for 31/2 hours. After cooling the reaction mixture was treated with 2N hydrochloric acid. Evaporation to dryness followed by recrystallisation from isopropanol/methanol gave 2-[2-(2-thiazolyl-methylthio)-ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 172.5°-174.5°.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:32][C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1cccs1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccs2)CC1
Yield: 99.9 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 2-thiophenecarboxaldehyde (0.64 g) were reacted and treated in the same manner as in Example 121 to give 2.5 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-thienylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=3)[C:17]([CH3:26])([CH3:25])[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].CO[C:42](=[O:58])[C:43]([CH3:57])([NH:45][CH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]=[CH:49][CH:48]=1)[CH3:44]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[C:42](=[O:58])[C:43]([CH3:44])([CH3:57])[N:45]([CH2:46][C:47]5[C:56]6[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=6)[N:50]=[CH:49][CH:48]=5)[C:28]4=[O:29])[CH:22]=3)[C:17]([CH3:26])([CH3:25])[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc(N)cc32)CC1
Reactant: COC(=O)C(C)(C)NCc1ccnc2ccccc12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc(N4C(=O)N(Cc5ccnc6ccccc56)C(C)(C)C4=O)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg 4-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester in 5 ml tetrahydrofuran 0.05 ml ethyl-diisopropylamine and 28 mg 4-nitrophenyl chloroformate were added and the mixture was stirred for 2 hours at room temperature. Afterwards 36 mg 2-methyl-2-[(quinolin-4-ylmethyl)-amino]-propionic acid methyl ester were added to the reaction mixture. After 16 hours stirring at room temperature the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid.