Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.Cl>O.CN(C)C=O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CC(C)CCNc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of N-(3-methylbutyl)-4-phenyl-1,3-thiazol-2-amine (370 mg), sodium hydride (60% oil, 50 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by preparative HPLC (gradient cycle A) to give the title compound (250 mg, yield 47%) as a yellow oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (36 mg, 64%), MS (ISP) m/z=418.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (50 mg, 0.136 mmol) and 3-methoxypropionic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:25]>C(Cl)(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1nc2cccc(-c3ccc(CO)cc3)n2n1)C1CC1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nc2cccc(-c3ccc(CBr)cc3)n2n1)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform is slowly added phosphorus tribromide (1.0 eq.). The reaction mixture is stirred at room temperature for 20 h, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to dryness. The resulting white residue is triturated in dichloromethane/diethyl ether 2:1 to afford the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C[O:15][C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([CH:22]=[CH2:23])=[N:20][CH:21]=2)=CC=1>C1(OC)C=CC=CC=1>[CH3:24][C:18]1[CH:17]=[C:16]([OH:15])[CH:21]=[N:20][C:19]=1[CH:22]=[CH2:23]
Reactant: C=Cc1ncc(OCc2ccc(OC)cc2)cc1C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1ncc(O)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.25 mL, 5 times) was added to a stirred solution of 5-((4-methoxybenzyl)oxy)-3-methyl-2-vinylpyridine (250 mg, 0.00098 mmol) in anisole (0.5 mL). The reaction mixture was stirred for 2 h at ambient temperature. After completion of the reaction, the reaction mixture was concentrated and quenched with saturated NaHCO3 solution (2 ml). The reaction mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was triturated with pentane to afford 5-methyl-6-vinylpyridin-3-ol as an off white solid (100 mg, 76%). MS m/z=136.15 [M+H]+.
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][O:7][C:8](=[O:26])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[NH2:10].[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:30]=1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:26])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[NH:10][C:31](=[O:32])[C:30]1[C:34]([O:38][CH3:39])=[CH:35][CH:36]=[CH:37][C:29]=1[O:28][CH3:27]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
EDC (212 mg, 1.1 mmol) was added to a solution of (O-benzyl)tyrosine methyl ester hydrochloride (322 mg, 1 mmol), 2,6-dimethoxybenzoic acid (182 mg, 1 mmol), HOBT (149 mg, 1.1 mmol) and NMM (242 μl, 2.2 mmol) in DCM (10 ml). The mixture was stirred at room temperature overnight, then diluted with DCM (100 ml), washed with 10% citric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2; EtOAc/hexane, 60:40) to give the title compound as a colourless gum (392 mg, 87%). δH (CDCl3) 7.44-7.31 (5H, m, OCH2Ph), 7.29 (1H, t, 18.4 Hz, Ar(OMe)H), 7.14 (2H, d, 18.7 Hz, CH2Ar(O)H), 6.88 (2H, d, J 8.7 Hz, CH2Ar(O)H), 6.55 (2H, d, J 8.4 Hz, Ar(OMe)H), 6.36 (1H, br d, 17.4 Hz, CONH), 5.11 (1H, dt, J 7.5, 5.2 Hz, CHαtyr) 5.02 (2H, s, OCH2Ph), 3.80 (6H, s, 2×ArOMe), 3.72 (3H, s, CO2Me), 3.29 (1H, dd, J 5.5, 14.0 Hz. CHCHAHBAr) and 3.16 (1H, dd, J 4.9, 14.0 Hz, CHCHAHBAr); m/z (ESI, 15V) 450 (Mh+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14](Cl)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([CH:14]2[C:13]3[C:18](=[CH:19][C:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[CH:11][CH:12]=3)[O:17][CH2:16][CH2:15]2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCC2Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C2CCOc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Temperature: 70 °C
Yield: 52.9 %

Procedure:
7-Benzenesulfonyl-4-chloro-chroman (512 mg, 1.65 mmol), Boc-piperazine (piperazine-1-carboxylic acid tert-butyl ester, 371 mg, 1.92 mmol), sodium iodide (50 mg) and potassium carbonate (275 mg) were added to 5 mL of DMF, and the reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water, and the combined organic layers were dried over MgSO4. Solvent was removed under reduced pressure, and the residue was chromatographed (silica gel, using 30% ethyl acetate in hexanes) to yield 400 mg of 4-(7-Benzenesulfonyl-chroman-4-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
A solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.39 g) in methylene chloride (7.8 ml) was added dropwise to a solution of m-chloroperbenzoic acid (0.21 g) in methylene chloride (7.8 ml) at −40° C., and the mixture was stirred for 20 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 218) (146 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[C:2]([F:1])[CH:3]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of benzyl 2-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (8.7 g, 24.4 mmol) in tetrahydrofuran (90 mL) was added lithium hydroxide monohydrate (2.05 g, 48.8 mmol) in 90 mL of water (90 mL) and methanol (90 mL) was added until a transparent solution formed. This mixture was stirred at ambient temperature for 2 hours and acidified with 2N hydrochloric acid to pH=2. The mixture was concentrated to about 90 mL, diluted with water and left to stand at ambient temperature overnight. The solid was collected by filtration, washed with water and dried to give 4-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)-2-fluorobenzoic acid (8.4 g, yield 98%). LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:38]([S:44][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCS
Product: CCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with hexanthiol, mp 81°-83° C.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1)([O-:21])=[O:20]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Product: O=[N+]([O-])c1c(Nc2ccc3c(c2)OCCO3)ccc2c1CCCC2
Yield: 98.1 %

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate (3.25 g, 10 mmol) and 6-amino-2,3-dihydrobenzo[1,4]dioxin (1.51 g, 10 mmol) were used in a process similar to Example 1(1) to give the titled compound as red oil (3.20 g, yield 98%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[C:15]([O:18][CH2:19][CH2:20][C@@H:21]([NH:25][C:26]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:35][C:34]=2[O:44][CH3:45])=[C:30]([CH3:46])[N:29]=[C:28]([NH2:47])[N:27]=1)[CH2:22][CH2:23][CH3:24])(=[O:17])[CH3:16]>C1COCC1.O.C(OC([O-])=O)(O)=O.[Na+]>[C:15]([O:18][CH2:19][CH2:20][C@@H:21]([NH:25][C:26]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][O:43][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:35][C:34]=2[O:44][CH3:45])=[C:30]([CH3:46])[N:29]=[C:28]([NH2:47])[N:27]=1)[CH2:22][CH2:23][CH3:24])(=[O:17])[CH3:16]
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO)cc1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])OC(=O)O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCOS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.083 mL) was added to a solution of diisopropylethylamine (0.279 mL) and the product from step (iv) (0.246 g) in THF (10 mL). The mixture was stirred at RT for 3 h and additional diisopropylethylamine (0.14 mL) and methanesulfonyl chloride (0.042 mL) was added. The mixture was stirred at RT for 2 h, diluted with water and sat. sodium hydrogen dicarbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure to afford the crude product (300 mg) as a pale yellow oil, which was used for the next reaction without further purification; LC-MS: m/z 539.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([N:15]([CH2:32][CH3:33])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29](O)=[O:30])=[CH:24][CH:23]=[CH:22]2)[CH3:14].[NH2:34][C:35]([NH2:37])=[NH:36]>C1COCC1>[CH2:13]([N:15]([CH2:32][CH3:33])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([NH:36][C:35]([NH2:37])=[NH:34])=[O:30])=[CH:24][CH:23]=[CH:22]2)[CH3:14]
Reactant: CCN(CC)CCOc1ccc2c(C(=O)O)cccc2c1
Reactant: N=C(N)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(C(=O)NC(=N)N)cccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of CDI are added to a suspension of 2.0 g of 6-(2-diethylaminoethoxy)-1-naphthoic acid in 50 ml of THF, and the reaction mixture is stirred at RT overnight. It is then treated with 2.0 g of guanidine, again stirred overnight and concentrated, and the residue is stirred with 100 ml of water. The precipitate formed is filtered off with suction and purified by FC using methylene chloride/methanol 1:1.0.66 g of 6-(2-diethylaminoethoxy)-1-naphthoylguanidine is obtained; m.p.: 168-169° C. 1H-NMR (DMSO-d6): δ [ppm]=1.0 (6H), 2.6 (4H), 2.85 (2H), 4.15 (2H), 7.15 (1H), 7.3 (1H), 7.4 (1H), 7.75 (2H), 8.7 (1H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:9]3[CH2:12][CH2:13][CH2:14][CH2:15][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]([C:16]2[CH:17]=[C:18]([N:22]([CH3:35])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:19]=[CH:20][CH:21]=2)[C:3]1=[O:36].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[ClH:50].CO>C(Cl)(Cl)Cl.CO.CN(C=O)C>[ClH:50].[CH3:35][NH:22][C:18]1[CH:17]=[C:16]([N:4]2[C:5]3[CH:6]=[CH:7][C:8]4[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=4[C:10]=3[NH:11][C:2](=[O:1])[C:3]2=[O:36])[CH:21]=[CH:20][CH:19]=1
Reactant: CN(c1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of N-[3-(2,3-dioxo-2,3,7,8,9,10-hexahydrobenzo[f]quinoxalin-4(1H)-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide (35 mg, 0.070 mmol), thiophenol (8.5 μL, 0.083 mmol), potassium carbonate (29 mg, 0.210 mmol), and dry DMF (1 mL) was stirred at room temperature for 18 hours. To the reaction solution was added ice-cold water. The precipitated crystal was collected by filtration, washed with water, and dried. The obtained crude compound was suspended in a methanol (1 mL) and 2M hydrogen chloride/methanol solution (40 μL). To the suspension was added chloroform to form a solution. The solvent was removed by evaporation under reduced pressure. To the obtained residue was added water, and concentrated again to obtain the titled compound as a pale yellow crystal (15 mg, yield 71%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH3:17])=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4].[C:18]([OH:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:26][CH2:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH3:17])=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1cc(C(=O)CCl)c(N(C)C=O)cc1C
Product: COc1cc(C(=O)COC(=O)c2ccccc2)c(N(C)C=O)cc1C

Procedure:
The solution of 2'-(2-chloroacetyl)-4'-methoxy-5'-methyl-N-methylformanilide may be reacted with benzoic acid by a method analogous to that of Example 2(d) to give the novel compound 2-[5-methoxy-4-methyl-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate.
Reaction SMILES: CO[CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C[Si]([C:17]#[N:18])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>[I-].[Zn+2].[I-].C(#N)C>[CH3:12][O:11][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)[CH2:17][NH2:18]
Reactant: COC(OC)c1cccc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CC#N
Product: COC(CN)c1cccc(Br)c1

Procedure:
1-Methoxy-1-(3-bromophenyl)acetonitrile was prepared from 3-bromobenzaldehyde dimethyl acetal and trimethylsilyl cyanide, using zinc iodide as catalyst, by an analogous procedure to that described in Example X1. Reduction of the acetonitrile with lithium aluminium hydride by an analogous procedure to that described in Example X2 gave the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:2]1>[Pd].CO.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1
Reactant: O=C(O)/C=C\c1csc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1csc2ccccc12
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A suspension of 329a (5.5 g, 27 mmol) and 10% Pd/C (600 mg) in 1:1 methanol/ethyl acetate (100 mL) was hydrogenated in a Parr apparatus at 50 psi for overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give crude 329b as a brown solid (5.0 g, 90%), which was used without further purification for the next step. MS: [M+H]+ 207. 1H NMR (500 MHz, CDCl3) δ 2.81-2.84 (t, J=8.5, 2H), 3.18-3.21 (m, 2H), 7.16 (s, 1H), 7.34-7.41 (m, 2H), 7.74-7.76 (d, 1H), 7.85-7.87 (d, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Cl.CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2cncn2)cc1
Yield: 44.5 %

Procedure:
A mixture of 13.8 parts of 1H-1,2,4-triazole, 18.7 parts of 1-bromo-4-methoxybenzene, 5 parts of potassium carbonate, 0.5 parts of copper (I)chloride and 90 parts of N,N-dimethylformamide is stirred and refluxed for 2 days. The reaction mixture is cooled and poured onto water. The product is extracted twice with benzene. The combined extracts are washed with water, dried filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7.8 parts (44.5%) of 1-(4-methoxyphenyl)-1H-1,2,4-triazole; mp. 99.4° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:3]=1.[CH:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[CH2:32].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C.CN(C=O)C>[N:36]1[CH:37]=[CH:38][C:33](/[CH:31]=[CH:32]/[C:2]2[C:10]3[C:5](=[CH:6][C:7]([C@H:11]4[C@@:13]5([C:21]6[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=6)[NH:15][C:14]5=[O:22])[CH2:12]4)=[CH:8][CH:9]=3)[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:3]=2)=[CH:34][CH:35]=1
Reactant: C=Cc1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)cc21
Temperature: 130 °C
Yield: 89.9 %

Procedure:
To a solution of (1R*,2S*)-2-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (375 mg, 0.7 mmol), 4-vinylpyridine (110 mg, 1.05 mmol), diisopropylethylamine (0.25 mL, 1.4 mmol) and DMF (2.5 mL) was added Pd(OAc)2 (8 mg, 0.035 mmol) and P(o-Tol)3 (22 mg, 0.07 mmol). The mixture was heated under microwave irradiation (130° C.) for 2 h. Ethyl acetate (150 mL) was added and the solution was washed with water (2×20 mL) and brine (20 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (1:1 Hexane/EtOAc to 100% EtOAc) to give the title compound as a beige solid (320 mg, 90%). MS ESI 509.3 [M+H]+, calcd for [C30H32N4O2Si+H]+ 509.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:25]=[C:24]([Cl:40])[N:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:40][C:24]1[N:23]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:27]=[C:26]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:25]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)nc(Cl)n2)cc2oc(=O)[nH]c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3nc(Cl)cc(Oc4cc(C)c5[nH]c(=O)oc5c4)n3)CC1)C(=O)N2

Procedure:
180 mg (0.65 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 205 mg (0.66 mmol) 6-(2,6-dichloropyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.25 mL (1.44 mmol) DIPEA in 5.0 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried. The substance was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.