Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1CCCl.N1(C2C3C=CC=CC=3SN=2)CCNCC1.[Na+].[I-].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)C.O.CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: O=C1Cc2ccc(Cl)cc2N1
Temperature: 120 °C

Procedure:
A reactor is loaded with 131 g (0.57 mol) of 6-chloro-5-(2-chloro-ethyl)-1,3-dihydro-indol-2-one, 125 g (0.57 mol) of piperazinyl benzoisothiazole, 260 ml of dimethylsulfoxide, 26 ml of water and 4.3 g (0.0285 mols) of NaI. The reaction mixture is added with 103 g (0.969 mol) of Na2CO3, with stirring under nitrogen atmosphere. The resulting mixture is heated to about 115-125° C. in 1 h and kept at said temperature under stirring for approx. 1 hr 45 min, then cooled and slowly added in about 25 min with isopropyl alcohol (650 ml), at a temperature of about 110° C., then slowly cooled at 25° C. The filtrate and the precipitate are washed with isopropyl alcohol (2×130 ml) to obtain 310 g of 5-(2-(4-benzo[d]isothiazol-3-yl) piperazin-1-yl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one free base, as a crystalline solid. The resulting product is placed in a 3 L beaker with 1500 ml of purified water, and 150 ml of 32% HCl are dropped therein with stirring. The reaction mixture is kept under stirring for 10 min, filtered, washed with purified water (2×500), dried to give 260 g of 5-(2-(4-benzo[d]isothiazol-3-yl) piperazin-1-yl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride, as a crystalline solid.
Reaction SMILES: [CH2:1]([S:17]([O-])(=[O:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Ag+:21]>O>[CH2:1]([S:17]([O-:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Ag+:21]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)[O-]
Agent: [Ag+]
Solvent: O
Product: CCCCCCCCCCCCCCCCS(=O)[O-]

Procedure:
5 g of silver hexadecylsulfonate was mixed with 12.5 mL of a 10% by weight aqueous solution of the non-ionic surfactant NON 03 and 82.5 g of deionized water in a ball mill to produce a fine and stable dispersion of silver hexadecylsulfinate.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: CN1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Product: CN1CCN(c2ncc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)s2)CC1

Procedure:
2-(4-Methyl-piperazin-1-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and 4-methylpiperazine. MS calcd. for C25H24ClN5O2S [(M+H)+] 494.1, obsd. 494.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:16][C:17](=[O:26])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]#[CH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:19]([N:18]1[C:14](=[CH2:15])[C:11]2([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[O:16][C:17]1=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C#CC1(OC(=O)NCc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C1N(Cc2ccccc2)C(=O)OC12CCN(Cc1ccccc1)CC2
Temperature: 0 °C
Yield: 83 %

Procedure:
A solution containing 34.8 g of 1-benzyl-4-benzylcarbamoyloxy-4-ethynylpiperidine and 1.1 g of sodium methoxide in 350 ml of anhydrous methanol is refluxed for 4 hours. After cooling down and maintaining the reaction mixture at 0° C. for 30 to 60 minutes the crystalline precipitate is filtered and recrystallized from methanol to obtain the title compound in 83% yield, m.p.: 113°-114° C.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][C@H:61]([O:64][C:65]2[C:66]3[CH2:74][NH:73][CH2:72][CH2:71][C:67]=3[N:68]=[CH:69][N:70]=2)[CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>O1CCOCC1>[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][C@H:61]([O:64][C:65]2[C:66]3[CH2:74][N:73]([C:2]4[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=4)[CH2:72][CH2:71][C:67]=3[N:68]=[CH:69][N:70]=2)[CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Reactant: COc1ncc(Br)c(OC)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)c(OC)n1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
5-Bromo-2,4-dimethoxy-pyrimidine (89 mg, 0.41 mmol), X-Phos (46 mg, 0.09 mmol) bis(dibenzylideneacetone)palladium(0) (29 mg, 0.03 mmol), cesium carbonate (203 mg, 0.62 mmol) were combined and flushed 10 min with Argon. To this mixture was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (100 mg, 0.31 mmol) in dioxane (4 mL), the vial was capped and the reaction mixture was stirred at 120° C. for 4.5 h. The mixture was allowed to cool to rt and filtered through a celite pad. The filtrate was diluted with EtOAc (20 mL) and washed with sat. NaHCO3(aq) (10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Dissolved in dioxane (4 mL) and added to a glass vial containing 5-bromo-2,4-dimethoxy-pyrimidine (89 mg, 0.41 mmol), X-Phos (46 mg, 0.09 mmol) tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.03 mmol), cesium carbonate (203 mg, 0.62 mmol). The vial was capped and the reaction mixture was stirred at 120° C. for 4.5 h. The mixture was allowed to cool to rt and filtered through a celite pad. The filtrate was diluted with EtOAc (20 mL) and washed with sat. NaHCO3(aq) (10 mL) then brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give (S)-3-(6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester which was used without further purification. (S)-3-(6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2 (2.0 mL) and TFA added (1 mL). The resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated in vacuo. Purification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions by PL-HCO3 cartridge & lyophilisation gave 6-(2,4-dimethoxy-pyrimidin-5-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow powder (11 mg, 10% yield over 2 steps). LCMS: [M+H]+=359.1, Rt(2)=0.79 min
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:16]1[N:34]=[C:19]2[C:20]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:20]2[C:19]3[N:18]([N:17]=[C:16]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:9][CH:10]=4)[N:34]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Product: COc1ccc(CNc2cccn3nc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)cc1

Procedure:
N(8)-(4-Methoxy-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (74.2 mg, 0.388 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product was isolated as a red foam (10.64 mg, 7%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.03 (s, 1H), 7.92 (d, J=6.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 6.88 (d, J=8.3 Hz, 4H), 6.68 (t, J=13.9, 7.0 Hz, 1H), 6.29 (m, 2H), 4.42 (m, 2H), 3.72 (s, 3H), 3.03 (s, 4H), 2.47 (s, 4H), 2.22 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([OH:14])[CH2:11]1)(C(C)(C)C)(C)C.O[CH:24]1CC(C([O-])=O)C1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.C[O+](C)C>C(Cl)Cl.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([O:14][CH3:24])[CH2:11]1
Reactant: O=C([O-])C1CC(O)C1
Reactant: CC(C)(C)OC(=O)NC1(CO[Si](C)(C)C(C)(C)C)CC(O)C1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC1CC(CO)(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
500 mg (1.51 mmol) of tert-butyl 1-((tert-butyldimethylsilyloxy)methyl)-3-hydroxycyclobutylcarbamate (prepared by reduction of ethyl-1[[tert-butyloxy)carbonyl]amino]-3-hydroxycyclobutane-1-carboxylate as described in J. Med. Chem., 1990 33(10) 2905-2915) and proton sponge (N,N,N′,N′ tetramethylnapthalene-1,8 diamine) (1.63 g, 6.04 mmol) were dissolved in DCM (18 mL), cooled down to 0° C., and 447 mg (3.02 mmol) of trimethyloxonium borontetrafluoride was added in one portion as a solid under vigorous stifling. The reaction mixture was stirred for 3 h and diluted with DCM (50 mL) and brine (20 mL), added under vigorous stifling. The organic phase was washed with sodium bicarbonate, brine, dried over sodium sulphate, evaporated and purified on short silica column (DCM as an eluent). The resulting product was dissolved in THF (5 mL), and a solution of tetrabutylammonium fluoride in THF (1M, 4.5 mL) was added, and the reaction was stirred at room temperature for 4.5 h. The reaction was monitored by TLC and once deemed to have reached completion, it was absorbed onto silica and purified on silica (EtOAc-hexane 1:1 to neat EtOAc) to give the title compound (251 mg, 72%). LC/MS 232 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13](=[O:21])[N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[O:21]=[C:13]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:31]
Reactant: NCC(=O)N(CC(=O)N1CCCCCC1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCCCC2)c2ccccc2)c1
Yield: 51.6 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.2 g of 2-amino-N-[2-oxo-2-(1perhydroazepinyl)ethyl]-N-phenylacetamide and 0.55 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from a mixture of dimethylformamide and ethyl acetate (63-35 by volume), 0.9 g of N-[2-oxo-2-(1-perhydroazepinyl)ethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 245° C. is obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]1=[O:16])C>O1CCCC1>[O:16]=[C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CCOC(CCCN1CCCCCOC1=O)OCC
Solvent: C1CCOC1
Product: O=CCCCN1CCCCCOC1=O
Yield: 99.7 %

Procedure:
A mixture of 3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2 g, 7.3 mmole) and 1.5 g Dowex 50W2-200 ion exchange resin in 3% aqueous tetrahydrofuran (30 mL) was heated under reflux for 24 hours. The mixture was filtered, and the filtrate was concentrated and dissolved in dichloromethane. The solution was dried with magnesium sulfate and concentrated to give 4-(2-oxo-[1,3]oxazocan-3-yl)-butyraldehyde (1.45 g) as a viscous oil which solidified.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C@H:37]([C:40](O)=[O:41])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C@H:37]([C:40](=[O:41])[NH:27][CH2:26][CH2:25][CH2:24][NH:23][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)C1
Yield: 90.2 %

Procedure:
A stirred suspension of 2-[2-(3-aminopropylamino)-5-chloropyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 1.24 mmol) in dichloromethane (30 mL) is treated at room temperature with (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (333 mg, 1.55 mmol), N,N-diisopropylethylamine (0.220 mL, 1.26 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol) and 1-hydroxybenzotriazole (171 mg, 1.21 mmol) for 24 hours. The mixture is then diluted with dichloromethane (30 mL), filtered, washed with water (30 mL) and diethyl ether (30 mL), and dried to provide (S)-3-{3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propylcarbamoyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 90%). A stirred mixture of this intermediate (665 mg, 1.11 mmol) in dichloromethane (25 mL) is treated at room temperature with TFA (2.5 mL) for 72 hours. The mixture is then concentrated under reduced pressure and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 16-40%, to provide the title compound (474 mg, 82% yield). ES+(m/z) 499 (35Cl) and 501 (37Cl) [M+H].
Reaction SMILES: Br[CH2:2][C:3](CBr)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1C=CC=C1C(O)=O>>[CH3:2][C:3]([O:35][C:33]1[O:34][CH:30]=[CH:29][CH:28]=1)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:18])[CH3:19])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CBr)CBr
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Agent: O=C(O)c1ccco1
Product: CC(=O)Oc1ccco1

Procedure:
(Electrospray MS m/z 514 [MH+ ]) from of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone and 2-furan carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:17][CH:16]=2)[C@H:10]([O:34][CH2:35][C@H:36]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:44][C:45]1[CH:46]=[C:47]([O:55][CH3:56])[C:48]2[C:53]([CH:54]=1)=[CH:52][CH:51]=[CH:50][CH:49]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:44][C:45]2[CH:46]=[C:47]([O:55][CH3:56])[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:54]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:17][CH:16]=2)[C@H:10]([O:34][CH2:35][C@H:36]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CCl)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3C#N)cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1 (α)] to yield the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 753 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH2:27])[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:35][CH2:36][O:37][C:38]1[C:42](=O)[C:40](=[O:41])[C:39]=1[O:44]CC.C(OCC)(=O)C>C(O)C.CCCCCC>[CH2:36]([O:37][C:38]1[C:39](=[O:44])[C:40](=[O:41])[C:42]=1[NH:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:35]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOc1c(Nc2cnn(C)c2NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine 1.60 g) in ethanol (50 ml) were added triethylamine (0.627 ml) and diethyl squarate (0.858 ml), and the mixture was stirred at room temperature for 22 hours. To the reaction mixture were added ethyl acetate (200 ml) and hexane (100 ml), and the solution was washed successively with water, 5% aqueous citric acid solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crystalline residue was washed with diethyl ether and dried in vacuo to give 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (1.45 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>C1COCC1.C(Cl)Cl.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:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccc(F)cc3)n2)ccc1F
Temperature: 50 °C

Procedure:
To a mixture of 4,2′-difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.11 g, 0.32 mmol), cuprous 3-methylsalicylate (0.153 g, 0.711 mmol) and 4-fluorobenzeneboronic acid (0.1 g, 0.711 mmol) in dry THF (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.032 mmol) and the mixture heated at 50° C. for 5 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and filtered through a glass fibre filter. The dark brown solution was evaporated to give a brown solid. The crude product was chromatographed on silica (eluted with 3% MeOH in DCM) to give the product as a yellow solid. Recrystallisation from DCM/MeOH gave the title compound as a pale yellow solid (52 mg): δH (400 MHz, CDCl3) 7.24 (2H, m), 7.44-7.49 (2H, m), 7.55-7.62 (2H, m), 8.36-8.39 (2H, m), 8.64-8.69 (2H, m), 9.62 (1H, s); m/z (ES+) 389 (M++H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:22]1=[O:37])[CH3:20].[H-].[Na+]>>[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:2]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]4[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=4[N:3]=3)=[CH:34][CH:35]=2)[C:22]1=[O:37])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 200 °C
Yield: 94.5 %

Procedure:
2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.4 g) and sodium hydride (0.263 g) in DMF(dry) (10 mL) at room temperature. The mixture was heated at 200° C. for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of 1-ethyl-3-{4-[(1-{([2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)no1
Yield: 57.1 %

Procedure:
4.8 gm (0.015 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.11 gm (0.021 mol) of 3-amino-5-methyl-isoxazole in 250 ml of dry xylene analogous to Example 1, yielding 3.3 gm (57% of theory) of 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 253° C, after recrystallization from xylene.