Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([Br:31])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([Br:31])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:22][CH2:23][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:29][CH2:30]1)[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(Br)cc1NC1CCC2(CC1)OCCO2
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 16 h

Procedure:
The 1M solution of trans-4-methylcyclohexyl carboxylic acid chloride is added to a solution of 5-bromo-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (24.79 g, 65 mmol) in toluene (25 mL) followed by pyridine (5.78 mL, 71.5 mmol). The resulting mixture is then stirred for 16 h at reflux. The reaction mixture is diluted with toluene (60 mL) and cooled down to 5° C. After the addition of pyridine (12 mL) and MeOH (5.6 mL), the mixture is stirred 2 h at 5° C. The white suspension is filtered off and the toluene is added to the mother liquor. The organic phase is washed with 10% citric acid, aq. Sat NaHCO3, dried (Na2SO4) and concentrated. The residue is triturated in boiling hexane (1500 mL). The reaction mixture is allowed to cool down to room temperature. The reaction flask is immersed into ice bath, and stirred for 30 min; white solid is filtered off, and washed with cold hexane (225 mL). The solid is purified by silica gel column chromatography using 20% EtOAc:hexane as eluent to furnish the final compound 5-bromo-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10.5 g, 32%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH2:29][CH2:28][C:27]=3[CH:31]=2)[CH2:19][CH2:18]1)([OH:3])=O.CS([O-])(=O)=O.ClC1C=CC=C[N+:39]=1C.N>CN1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH2:29][CH2:28][C:27]=3[CH:31]=2)[CH2:19][CH2:18]1)(=[O:3])[NH2:39]
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CN1CCCC1
Agent: CS(=O)(=O)[O-]
Agent: N
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.8 g of 1-[4-(5-carboxyindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)piperazine are suspended in 100 ml of N-methylpyrrolidine. 3.2 g of 2-chloro-1-methylpyridinium methanesulfonate are then added and the mixture is stirred at room temperature for 12 hours. Dried NH3 gas is then passed into the resulting solution until it is saturated and the mixture is stirred again for 10 hours. Customary working up gives 1-[4-(5-carbamoylindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)-piperazine.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[C:10]([NH2:16])(=[O:15])[CH2:11][C:12](N)=[O:13].S(=O)(=O)(O)O.N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:5][Si:4]([CH3:7])([CH3:6])[NH:16][C:10](=[O:15])[CH2:11][C:12]([NH:3][Si:4]([CH3:5])([CH3:6])[CH3:7])=[O:13]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC(=O)CC(N)=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[Si](C)(C)NC(=O)CC(=O)N[Si](C)(C)C
Yield: 99004.2 %

Procedure:
7.5 ml (36 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 3.06 g (0.03 mmole) of malonamide, 18.3 mg (0.1 mmole) of saccharin, 50 ml of ethyl acetate and 5 ml of pyridine and by titrating with 1 N sulfuric acid the ammonia evolved, it was found that 30 mmoles were expelled after refluxing for one hour. Volatile material was vacuum evaporated and the residue, which crystallized upon standing, was dried in vacuo to obtain 7.32 g (99%) of N,N'-bis-(trimethylsilyl)-malonamide melting at 72°-76° C. NMR Spectrum (CDCl3): Δ0.24 (s, 18H); 3.20 (s, 2H); 6.5 (broad, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[N:13]3[C:14]([CH3:27])=[C:15](SC4C=CC=CC=4)[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[N:1]1([CH2:7][CH:8]2[N:13]3[C:14]([CH3:27])=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1c(Sc2ccccc2)c2cccc3c2n1C(CN1CCOCC1)CO3
Agent: [Ni]
Solvent: CCO
Product: Cc1cc2cccc3c2n1C(CN1CCOCC1)CO3
Yield: 61.6 %

Procedure:
To a solution of 10.6 g (0.028 mole) of 3-(4-morpholinylmethyl)-5-methyl-6-phenylthio-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine in 600 ml of ethanol was added seven teaspoons of Raney nickel. The mixture was heated under reflux for two hours and then filtered through filter aid. Evaporation of the filtrate to dryness and recrystallization of the residue from ethyl acetate afforded 4.7 g of 3-(4-morpholinylmethyl)-5-methyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine, m.p. 178°-180° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:17][OH:18])[O:4][C@H:5]2[N:9]1[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]1=[O:11].[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([O:18][CH2:17][C@@:3]23[C@@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:4]3)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 44 (0.08 g, 0.31 mmol) in anhydrous pyridine (0.5 cm3) was added 4,4′-dimethoxytrityl chloride (0.203 g, 0.6 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction was quenched with ice-cold water (10 cm3) and extracted with dichloromethane (3×4 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogencarbonate (3×3 cm3) and brine (2×3 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 45 as a white solid material (0.12 g, 69%). δH (CDCl3) 9.25 (1H, br s, NH), 7.93 (1H, d, J 7.2, 6-H), 7.50-7.15 (9H, m, DMT), 6.88-6.78 (4H, m, DMT), 5.63 (1H, s, 1′-H), 5.59 (1H, d, J 8.0, 5-H), 4.48 (1H, s, 2′-H), 4.26 (1H, s, 3′-H), 3.88 (1H, d, J 8.1, 1″-Ha), 3.85-3.55 (7H, m, 1″-Hb, OCH3), 3.58-3.40 (2H, m, 5-Ha, 5′-Hb). δC (CDCl3) 164.10 (C-4), 158.60 (DMT), 150.45 (C-2), 147.53 (DMT), 144.51 (C-6), 139.72, 135.49, 135.37, 130.20, 129.28, 128.09, 127.85, 127.07 (DMT), 113.39, 113.17 (DMT), 101.79 (C-5), 88.20, 87.10, 86.87 (C-1′, C-4′, DMT), 79.25, 71.79, 69.70, 58.13 (C-2′, C-3′, C-5′, C-1″), 55.33 (OCH3). FAB-MS m/z 559 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:11]1([C:9]2[N:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]3=[CH:7][N:8]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCc1ccccn1)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(-c3ncc4ccccn34)cccc2c1
Temperature: 90 °C
Yield: 72.3 %

Procedure:
To a solution of naphthalene-1-carboxylic acid (pyridin-2-ylmethyl)-amide (2.80 g, 10.7 mmol) in toluene (100 mL) was added POCl3 (9 mL). The mixture was heated to 90° C. for 12 h. After this time the mixture was allowed to cool and poured slowly into 10% aqueous potassium carbonate (500 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield 3-naphthalen-1-yl-imidazo[1,5-a]pyridine (1.89 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (9.35 g, 34.1 mmol) in THF (170 mL) was added ethylmagnesium bromide (1M solution in THF) (136 mL, 136 mmol) dropwise at 0° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred for 4 hr. At this time, only 50% of the starting material was consumed. The reaction mixture was cooled again to 0° C. To push the reaction to completion, a 3M solution of ethylmagnesium bromide in diethyl ether (50 mL, 150 mmol) was added slowly to the cooled reaction mixture. The reaction was quenched with an aqueous solution of 1N HCl at 0° C. and was extracted with ethyl acetate. The combined organic layer was washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography (100% hexanes ramped to 6% ethyl acetate in hexanes) to give 1-(4-fluoro-2-phenylamino-phenyl)-propan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@:4]([C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:13][C:14]1[N:18]=[C:17]([CH:19]([OH:21])[CH3:20])[NH:16][CH:15]=1)[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[S:42](Cl)([C:45]1[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:41])[C@:4]([C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:13][C:14]1[N:18]=[C:17]([CH:19]([O:21][S:42]([C:45]2[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH3:20])[NH:16][CH:15]=1)[N:5]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@](Cc1c[nH]c(C(C)O)n1)(N=Cc1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@](Cc1c[nH]c(C(C)OS(=O)(=O)c2ccc(C)cc2)n1)(N=Cc1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To the solution of compound 2.III from Step C is added 0.5 ml of pyridine and then 190.5 mg (1 mmole) of tosyl chloride. After 30 minutes at 25° C. the solution is washed three times with water, once with brine, and dried with K2CO3 and filtered. The filtrate is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>N1C=CC=CC=1.CCOC(C)=O>[CH:14]1[C:13]2[C:18](=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH:16][C:15]=1[NH:19][C:20]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:21]
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2ccccc2c1)n1nc(O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 157 %

Procedure:
2-Amino-4-chloro-benzoic acid (17.16 g, 100 mmol) was suspended in 90 ml of water and 20 ml of concentrated HCl. NaNO2 (6.9 g, 100 mmol) was dissolved in 15 ml water and added slowly at 0° C. The mixture was stirred at 0° C. for 30 minutes and Na2SO3 (34.0 g, 270 mmol) were added, dissolved in 150 ml water. The mixture was then stirred for 2 hours at room temperature. 30 ml of concentrated HCl were added and the mixture stirred overnight at room temperature and then at 80° C. for 2 hours. The solution is treated with aqueous NaOH until the pH is 5.5 and the precipitated was filtered and triturated with ethanol to yield 13.8 g (82%) of 6-chloro-1H-indazol-3-ol. 6-Chloro-1H-indazol-3-ol (700 mg, 4.15 mmol) was dissolved in 25 ml pyridine together with 1-bromo-3-isocyanato-benzene (990 mg, 5 mmol) and stirred at RT for 4 hours. The mixture was then diluted with EtOAc (100 ml) and washed 2× with 1 M HCl. The organic phase was dried with Na2SO4 and reduced under vacuum. The residue was now dissolved in 1 M NaOH and washed with EtOAc and then precipitated with HCl and the precipitate extracted into EtOAc, dried and reduced under vacuum. The product was then recrystallised from EtOAc and heptane to yield 1.1 g (79%) of crystalline solid (m.p. 223-225° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH:14]C(=O)OC(C)(C)C)[CH2:10][N+:11]([O-:13])=[O:12]>O1CCOCC1.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH2:14])[CH2:10][N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(C[N+](=O)[O-])c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 ml of a 4 N solution of hydrogen chloride in dioxane were added to a solution of 1.037 g (3.45 mmol) of tert-butyl [1-(2-chlorophenyl)-2-nitroethyl]carbamate [see, for example, Tetrahedron Lett. 2009, 50 (9), 1016] in 10 ml of dichloromethane, and the mixture was stirred at RT for 2 h. The volatile components were then removed on a rotary evaporator. 5 ml of dichloromethane were added to the residue, and the mixture was once more freed from the solvent on a rotary evaporator and then dried under high vacuum. This gave 898 mg of the title compound (quant., still contains about 8% dioxane according to 1H NMR).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:21]([NH2:27])[CH:22]1[O:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:27][CH2:21][CH:22]4[CH2:23][CH2:24][CH2:25][O:26]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: NCC1CCCO1
Product: Brc1cnc2[nH]c(-c3ccc(OCCNCC4CCCO4)cc3)nc2c1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(2-chloroethoxy)phenyl)-3H-imidazo[4,5-b]pyridine and tetrahydrofurfurylamine.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH2:3][S:4][C:5](=[O:7])[CH3:6].[OH-].[Li+].[C:31](Cl)(=O)[CH2:32][CH2:33]CC.O>CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH2:3][S:4][C:5](=[O:7])[CH2:6][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)SCC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCCCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC(=O)SCC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
Thioacetic acid S-{2-oxo-2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}ester (SI-4) (0.5 g, 1.15 mmol) was dissolved in anhydrous DMF (5 ml). Lithium hydroxide (28 mg, 1.15 mmol) was added and the solution was sonicated until homogeneous and heated to 90° C. for 4 hours. The solution was allowed to cool to room temperature and valeryl chloride (150 mg, 1.27 mmol) was added and the mixture stirred for 16 hours. The solution was partioned between 20 ml each water and EtOAc. The organic layer was washed with water, then brine and dried over Na2SO4. The solution was then filtered, stripped of solevent and the product purified by flash chromatography (100% DCM). The solvent was evaporated to afford 107 mg (0.22 mmol, 19%) product as a clear oil. 1H-NMR: (400 MHz, DMSO): 8.07 (d, 2H), 7.60 (d, 2H), 7.40 (d, 2H), 7.25 (d, 2H), 2.40 (s, 2H), 2.10 (t, 2H), 1.42 (t, 2H) 1.11 (t,2H), 0.09 (t, 3H); LC-MS (ES+): 476 [M]+ m/e.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: Clc1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccccc1CC[C@H]1CNCCN1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-[2-(2-chloro-phenyl)-ethyl]-piperazine (2.59 g, 6.38 mmol) in dichloroethane (30 ml). Cool the solution to 0° and then add 1-chloroethyl chloroformate (2.74 g, 19.15 mmol) dropwise. Warm the solution to ambient temperature and then heat it at reflux for 15 hours. Remove the dichloroethane under vacuum and reflux the resulting residue in methanol for 1 hour. Remove the methanol under vacuum and dissolve the resulting precipitate in 1N NaOH. Extract the aqueous layer with dichloromethane and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90:10) to give 482.4 mg (34%) of the title compound: mass spectrum (ion spray): m/z=225.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:73]1[CH:77]=[CH:76][N:75]=[CH:74]1.CC(C)([O-])C.[Na+]>CN(C)C=O.C(=O)([O-])O.[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:73]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[CH:77]=[CH:76][N:75]=[CH:74]1
Reactant: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Reactant: c1c[nH]cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(-n4ccnc4)n3)c2)c1
Temperature: 180 °C
Yield: 40.2 %

Procedure:
A mixture of (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-3-methylbenzamide (92 mg, 0.25 mmol), palladium acetate (3 mg, 0.0125 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8 mg, 0.0125 mmol), imidazole (17 mg, 0.25 mmol) and sodium tert-butoxide (36 mg, 0.375 mmol) in N,N-dimethyl formamide (0.5 mL) was heated in a microwave reactor at 180° C. for 20 minutes. After this time the mixture was allowed to cool to room temperature and was diluted with saturated aqueous sodium hydrogen carbonate (10 mL), extracted with ethyl acetate (3×15 mL), washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give (S)—N-(3-(1-(6-(1H-imidazol-1-yl)pyrazin-2-ylamino)ethyl)phenyl)-3-methylbenzamide (40 mg, 40%) as a brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)=[CH:8][CH:7]=3)[C:12](=[O:25])[CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 45 mg (0.13 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-4-ylmethoxy)-1H-pyridin-2-one (example 10.1a) in 3.0 mL DCM is added at RT 56 μL (0.40 mmol) triethylamine and subsequently 21 μL (0.27 mmol) methanesulfonyl chloride. The reaction mixture is stirred 1 h at RT. Additional 56 μL triethylamine (0.40 mmol) and subsequently 21 μL (0.27 mmol) methanesulfonyl chloride are added at RT and the reaction mixture is stirred for additional 1.5 h. Then 22 μL (0.27 mmol) pyrrolidine is added. The mixture is stirred overnight at RT, diluted with 50 mL DCM and is washed four times with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via chromatography (silica gel; DCM/MeOH/NH4OH 9:1:0.1 to 8:2:0.2).
Reaction SMILES: [NH:1]([C:8]1[CH:25]=[CH:24][C:11]2[C:12](=[O:23])[C:13]3[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:14]=3[CH2:15][CH2:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[NH:1]([C:8]1[CH:25]=[CH:24][C:11]2[C:12](=[O:23])[C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[CH2:15][CH2:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccccc3)cc1CC2
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccc(Nc3ccccc3)cc2CCc2ccc(O)cc21
Temperature: 0 °C

Procedure:
0.2 g (0.61 mmol) of 2-anilino-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one is dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are added and the mixture is refluxed for 6 h. The solution is hydrolyzed with 200 g of ice and the precipitate is filtered off. The product is obtained in the form of a white powder. C21H17NO2 (Mr=315.380)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 4-nitrobenzoic acid.