Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:10]2[CH:9]=[C:8]([C:11](O)=O)[NH:7][C:6]=2[C:5]([N:14]([CH3:23])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[CH:4]1)[CH3:2].Cl.C([S:44][CH2:45][CH2:46][NH2:47])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.O.CN(C)C=O.C(N(CC)CC)C>[S:44]1[CH2:45][CH2:46][N:47]=[C:11]1[C:8]1[NH:7][C:6]2[C:5]([N:14]([CH3:23])[S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:4][N:3]([CH2:1][CH3:2])[C:10]=2[CH:9]=1
Reactant: CCn1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc21
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCn1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCCS3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a mixture of 4-ethyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid (780 mg), 2-(tritylthio)ethaneamine hydrochloride (850 mg), 1H-1,2,3-benzotriazol-1-ol (370 mg), triethylamine (0.5 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (460 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a colorless oil. To a solution of triphenylphosphine oxide (1.8 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (555 μL) at 0° C., the mixture was stirred for 10 min, and the colorless oil was added. The reaction mixture was stirred at room temperature for 2 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-[5-(4,5-dihydro-1,3-thiazol-2-yl)-1-ethyl-1,4-dihydropyrrolo[3,2-b]pyrrol-3-yl]-N-methylthiophene-2-sulfonamide (260 mg, yield 30%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:20 to 1:3, volume ratio). melting point 163° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:18]4[CH:19]=[CH:20][S:16][CH:17]=4)[CH:22]=3)[CH2:28][CH2:29]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2cccc(-c3ccsc3)c2)CC1
Yield: 37.4 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (303 mg, 1.13 mmol), 1-[3-(3-thienyl)phenyl]piperazine (250 mg, 1.02 mmol) and diisopropylethylamine (0.356 ml, 2.05 mmol) in dimethylsulfoxide (3.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound 139 mg (37.3%) as solid product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[C:4]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1.C(N(CC)CC)C.[CH2:36]([O:38][CH2:39][C:40](Cl)=[O:41])[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][C:40]([NH:15][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:41])[CH3:37]
Reactant: CCOCC(=O)Cl
Reactant: Cc1cc(NCCOCCCc2cccnc2)c(N)c(Oc2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(NCCOCCCc2cccnc2)cc(C)nc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 6-methyl-2-phenoxy-N4-{2-[3-(pyridin-3-yl)propoxy]ethyl}pyridine-3,4-diamine (5.2 g, 14 mmol), anhydrous dichloromethane (40 mL), and anhydrous triethylamine (2.3 mL, 16.5 mmol) was cooled to 5° C. A solution of ethoxyacetyl chloride (1.77 g, 14.4 mmol) in dichloromethane (10 mL) was then added over a period of ten minutes, and the reaction was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane (25 mL), washed with aqueous saturated sodium bicarbonate (3×) and brine (3×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 5.8 g of 2-ethoxy-N-(6-methyl-2-phenoxy-4-{2-[3-(pyridin-3 -yl)propoxy]ethylamino}pyridin-3-yl)acetamide as an oil.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][Se:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>CC(OC)(C)C.[Cu]I.CN(C=O)C>[Br:7][C:6]1[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[CH:3][Se:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1c[se]cc1Br
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c[se]cc1Br
Temperature: 90 °C
Yield: 79.5 %

Procedure:
To a pressure vessel purged with N2 was added 3,4-dibromo-selenophene (3.69 g, 12.77 mmol), DMF (10.0 mL), triphenylphosphine (0.669 g, 2.55 mmol), copper(I) iodide (0.161 g, 0.843 mmol), diethylamine (dried over KOH, 20.0 mL, 191.55 mmol), (trimethylsilyl)acetylene (0.910 mL, 6.39 mmol), and palladium dichloride-bis-triphenylphosphine (0.592 g, 0.843 mmol). The reaction vessel was sealed and the mixture heated to 90° C. for 1 h. Upon cooling to room temperature, the reaction mixture was diluted with MTBE (100.0 mL) and was washed with 0.1 M HCl (3×50.0 mL). The combined aqueous layers were extracted with MTBE (50.0 mL). The combined MTBE extracts were quenched with saturated sodium bicarbonate (50.0 mL), dried over magnesium sulfate, and concentrated to an oil. The crude oil was purified by column chromatography (silica gel, cyclohexane) to provide (4-bromo-selenophen-3-ylethynyl)-trimethyl-silane (1.55 g, 5.08 mmol, 79.5 mol %): 500 MHz 1H NMR (CDCl3) δ 8.15 (d, J=2.9 Hz, 1H), 7.58 (d, J=2.9 Hz, 1H), 0.26 (S, 9h); 125 MHz 13C NMR (CDCl3) δ 135.4, 127.0, 126.4, 114.1, 99.8, 96.8, 0.2.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:1]12([C:11]([O:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=3)=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OCc1cccc(Oc2ccccc2)c1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 66 h
Yield: 98.7 %

Procedure:
1 g (5.03 mmol) of tricyclo[3.3.1.13,7 ]decane-1-carbonyl chloride, 1.01 g (5.04 mmol) of 3-phenoxybenzyl alcohol and 0.08 g (10.07 mmol) of anhydrous pyridine were dissolved in 30 ml of anhydrous benzene. The mixture was stirred at room temperature for 66 hours. Then the reaction was terminated. The resulting pyridine hydrochloride was removed by filtration and the filtrate was thoroughly washed with 1N hydrochloric acid, 5% sodium carbonate and then saturated saline solution, and dried over sodium sulfate. The solvent was removed to obtain 1.8 g of an oily material. Purification by column chromatography on silica gel employing a developer consisting of n-hexane and benzene (1:1) gave 1.69 g (yield 93%) of a colorless oily material.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53(c)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-2-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C.O>CN1CCCC1=O.CCCCCC>[CH3:25][N:26]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNc1ccccc1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(c1ccccc1)c1cc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)ncn1
Yield: 46 %

Procedure:
N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200 mmol) and N-methylaniline (107 mg, 1.00 mmol) were heated and stirred in 1-methylpyrrolidone (1 ml) at 130° C. for 36 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=1:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (38 mg, 0.092 mmol, 46%) as colorless crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][C:5]1[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([OH:10])=[O:9].C=O.F[C:22](F)(F)C(O)=O.[OH-].[Na+]>O1CCCC1.O>[CH3:3][N:4]([CH3:22])[C:5]1[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (1.4 g, 36 mmol) was carefully added to a suspension of 1.53 g (6.30 mmol) of 3-methylamino-2-methyl-4-methylsulfonylbenzoic acid and 1.8 g (60 mmol) of paraformaldehyde in 75 mL of dry tetrahydrofuran under a nitrogen atmosphere. A 30 mL aliquot of trifluoroacetic acid was then added dropwise over 1 hour. Gas evolution was vigorous at first, but then subsided as the grey-white suspension was allowed to stir at room temperature. After 8 hours, the reaction was found to be complete by high pressure liquid chromatographic analysis (HPLC). The mixture was poured into 90 mL of a 25 percent aqueous sodium hydroxide solution containing ice, diluted with water and washed with ethyl acetate. The aqueous solution was then acidified with concentrated aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic extract was mixed with dilute aqueous sodium bicarbonate solution and the aqueous phase was collected, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic extract obtained was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with a 1:1 mixture of ethyl acetate and petroleum ether containing 1 percent acetic acid, to obtain 1.49 g (92 percent of theory) of the title compound as a yellow syrup which solidified on standing and melted at 113-114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C)cc(F)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-methylbenzoic acid (1.50 g, 9.73 mmol, Oakwood) in Acetone (40 mL) was added Potassium carbonate (1.34 g, 9.73 mmol) followed by Methyl iodide (0.73 mL, 12 mmol). The reaction mixture was heated to 65° C. for 1 hour, heating discontinued and stirred overnight, then heating resumed at that temperature for a further 2 hours. Additional Methyl iodide (0.5 mL, 8 mmol) was added and heating was continued for 6 hours. Solids were removed by filtration and acetone was removed in vacuo. The residue was partitioned between 1N NaOH and ethyl acetate. The aqueous portion was extracted with a further two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, decanted and concentrated. The product so obtained was used without further purification (1.64 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.66-7.63 (m, 1H), 7.51 (d, 1H), 7.10-7.04 (m, 1H), 3.91 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[S:10][C:11]([C:20]([O:22]CC)=[O:21])=[C:12]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:13]=2)[CH2:5][CH2:4]1.[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33](NC1CCN(C2SC(C3NN=NN=3)=CN=2)CC1)=[O:34].[Li+].[OH-].C1COCC1>>[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[S:10][C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:13]=2)[CH2:7][CH2:8]1)=[O:34]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(-c4nnn[nH]4)s3)CC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1COCCOC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOCc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C(=O)O

Procedure:
Prepared in an analogous manner to Example 129 starting from ethyl 2-(4-aminopiperidin-1-yl)-4-[(2-methoxyethoxy)methyl]-1,3-thiazole-5-carboxylate hydrochloride (Intermediate 126) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3). The ester product was submitted to hydrolysis using LiOH/THF at 65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7].[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=1.C(OCC)(=O)C>CO.ClCCl>[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Cl:20][C:15]1[CH:14]=[C:13]([C@@:10]2([CH2:21][CH2:22][N:53]3[CH2:52][CH2:51][C:50]([C:46]4[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2cccnc2)CCNCC1
Agent: NC(=O)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid morpholine-amide to give, after chromatography on silica gel eluting sequentially with ethyl acetate, 2% methanol/dichloromethane, 5% methanol/dichloromethane, and then 7% methanol/dichloromethane, the title compound: Rf =0.44 (silica gel, methanol/dichloromethane/concentrated ammonia 10/90/0.5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Nc2ccccc2)nc1
Temperature: 25 °C

Procedure:
A suspension of 5-nitro-pyrimidin-2-ylamine (0.10 g, 0.71 mmol), bromobenzene (0.15 g, 0.96 mmol), Pd(OAc)2 (13 mg, 0.057 mmol), Xantphos (67 mg, 0.12 mmol) and potassium tert-butoxide (0.22 g, 2.0 mmol) in DMF (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 140° C. for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the crude product used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH:28]=O)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH2:28][NH:12][C:9]3[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=3)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CSCCOc1cnc(N)nc1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
A solution of 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.03 g, 5.55 mmol) obtained in Step 1 and 3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypicolinaldehyde (1.60 g, 6.10 mmol) obtained in Step 3 in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, and then added with sodium triacetoxyborohydride (1.24 g, 5.83 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform— The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.60 g, 67%) as pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[C:15]([O:19][C:20](=[O:39])[N:21]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C.ClCCl>[C:15]([O:19][C:20](=[O:39])[N:21]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3ccccc32)CC1
Reaction time: 4 h
Yield: 32.3 %

Procedure:
To 5 mL of dichloromethane solution containing 0.15 g of (2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.27 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 45 μL of acetic acid and 0.25 g of sodium triacetoxyborohydride were added and stirred for 4 hours. To the reaction mixture, water and ethyl acetate were added, neutralized with aqueous saturated sodium hydrogen carbonate solution, thereafter the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1], to give 0.13 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: O=Cc1ccccc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of 2-fluorobenzaldehyde (63.3 g, 495 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (66.8 g, 97%) which was obtained as a light yellow solid. MS m/e (EI): 139.0 [M].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O1CCOCC1.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([C:6]3[CH:25]=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:3]=[CH:4][C:5]=3[N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:8])[CH2:14][CH2:13]2)=[C:16]([F:24])[CH:17]=1)(=[O:23])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(N)ccc3N3CCOCC3)CC2)c(F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(NS(C)(=O)=O)ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 1-{4-[4-(5-Amino-2-morpholin-4-yl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (50 mg, 0.12 mmol) and triethylamine (33 ul, 0.234 mmol) in dioxane (1.5 ml) was added a solution of methanesulfonyl chloride (15 mg, 0.13 mmol) in dioxane (0.5 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred in water. The yellow solid was filtered, washed with water and dissolved in CH2Cl2. The solution was dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel eluent: Heptane/ethyl acetate 0%-100% (5 minutes) to provide the title compound (35 mg, 59%) as a yellow solid MS (m/e): 505.3 (M+H, 100%)