Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([Br:22])[N:3]=1.Cl>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([Br:22])[CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Br)nc(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cc(Br)nc(Br)c2)cc1
Yield: 86.5 %

Procedure:
6.2 g (0.0138 mol) of N-[4-(2,6-dibromo-pyridin-4-yl-sulfamoyl)-phenyl]-acetamide were dissolved in 138 ml of 1N NaOH and boiled at reflux for 2 hours. After cooling the mixture was adjusted to pH 6 with 2N HCl and the precipitate which separated was filtered off. The material on the suction filter was washed well with water and dried. It was subsequently chromatographed on silica gel with ethyl acetate/hexane 1:2 ->1:1. There were obtained 4.86 g (86%) of 4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 220-222° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)=[N:4][N:5]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[CH:6]=1
Reactant: Clc1ccc(-c2n[nH]cc2Cl)s1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cn1cc(Cl)c(-c2ccc(Cl)s2)n1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-3-(5-chloro-thiophen-2-yl)-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): 7.58 (s, 1H), 7.38–7.42 (d, 1H), 6.94–7.1 (m, 2H), 6.84–6.88 (dd, 2H), 4.96 (s, 2H), 3.62–3.81 (m, 4H), 3.02–3.14 (m, 4H). 13C NMR (400 MHz, CDCl3): 165, 158.8, 156.8, 142.4, 131, 126.8, 124.8, 119, 116, 115.6, 54, 52, 51.6, 46, 42.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[C:12]([N:17]=[C:18]([CH:22]1[CH2:24][CH2:23]1)OCC)(OCC)=[O:13]>CO.C(Cl)Cl>[CH:22]1([C:18]2[NH:17][C:12](=[O:13])[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[N:11]=2)[CH2:24][CH2:23]1
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)N=C(OCC)C1CC1
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(C2CC2)nn1-c1ccccc1[N+](=O)[O-]
Yield: 69 %

Procedure:
By the procedure of Example 4, Step C, 2-nitrophenylhydrazine was reacted with ethyl N-(carbethoxy)cyclopropanecarboximidate. After work-up, the residue was purified by flash chromatography on silica gel (150 mL for 2.0 mmole, eluted with 1.5% MeOH/CH2Cl2) to give the desired material as a yellow foam in 69% yield, homogeneous by TLC in 5% MeOH/CH2Cl2, mass spectrum (FAB) m/e 247 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH:30]([CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: Nc1ccccc1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCNc1ccccc1
Reaction time: 20 h
Yield: 38 %

Procedure:
Bromide (204) (75 mg, 0.17 mmol) prepared as described in example 173 was reacted with aniline according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give aniline (217) (30 mg, 38%) as a yellow powder, mp 240° C. (dec). 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.33 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.48 (m, 2H), 7.42 (m, 3H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (m, 2H), 6.52 (m, 3H), 5.70 (t, J=5.3 Hz, 1H), 4.59 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.3 Hz, 2H), 2.07 (m, 2H). Found: C, 74.00; H, 5.22; N, 8.76. C29H23N3O3.1/2H2O requires: C, 74.03; H, 5.14; N, 8.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13](N)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I:26]CI.N(OCCC(C)C)=O.Cl>[Cu]I.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([I:26])[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1C1=NCc2cnc(I)nc2-c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 49.6 %

Procedure:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluorophenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>C(O)C>[CH3:26][N:27]1[CH2:32][CH2:31][C:30]2[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:29]=2[CH2:28]1
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)CBr
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2

Procedure:
Preparation of the title compound was carried out according by using p-tolylhydrazine hydrochloride, ethyl bromoacetate, triethylamine and N-methyl-4-piperidone hydrochloride in ethanol to obtain ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with dichloromethane-hexane gradient.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].O>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([CH3:16])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 1.18 g (5.50 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-hydroxy-4,6-dimethylpyridine (15) in 20 mL of anhydrous THF were added 1.20 mL (10.10 mmol) of benzyl bromide followed by 440 mg (11.00 mmol) of 60% sodium hydride suspension in mineral oil. The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was poured into 150 mL of water and extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 4:1 gave the expected product as light yellow oil: yield 1.42 g (84%). 1H-NMR (CDCl3) δ 6.98 (s, 1H), 5.91 (s, 2H), 4.94 (s, 2H), 2.58 (s, 3H), 2.37 (s, 3H), 2.17 (s, 6H); 13C-NMR (CDCl3) δ 152.02, 151.03, 146.64, 141.95, 136.73, 128.60, 128.33, 127.89, 121.94, 106.44, 74.59, 19.48, 16.18, 13.08.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[H][H].[BH4-].[Na+]>[Pd]>[OH:11][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1
Reactant: [H][H]
Reactant: O=C1CC(=O)c2ccccc21
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CC(O)c2ccccc21
Yield: 95 %

Procedure:
A mixture of 73.25 g. (0.5 mole) of 1,3-indandione, 10.0 g. of 10% Pd on charcoal and 800 ml. of 2B-ethanol was added to the 1 liter flask of a Brown Hydrogenator, and hydrogen equivalent to 125 ml. of 1M sodium borohydride solution was added at room temperature and atmospheric pressure (0.5 mole H2). The solution was filtered through a bed of Celite Filter Aid, and the bed washed with ethanol. The ethanol solution was concentrated, and from the concentrate, a small amount of white solid separated, 1,3-indanediol, 1.6 g., m.p. 182°-187°. This by-product was filtered off and discarded. Evaporation of the filtrate gave 70.2 g. of nearly colorless oil (yield > 95%) which can be used directly in the aldehyde condensation. The IR spectrum of the product showed typical hydroxyl and carbonyl absorption.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([N:14]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[CH2:37]1[O:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][N:14]([S:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=3[CH3:28])(=[O:17])=[O:16])[C@H:10]([CH:11]([CH3:13])[CH3:12])[C:9]([OH:39])=[O:8])=[CH:31][C:32]=2[O:38]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)O)C(C)C)c(C)c1C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (4.7 g, 8.49 mmol) in a 4:1 mixture of ethanol/tetrahydrofuran (40 mL) was added 10% Pd/C (0.15 g). The reaction mixture was placed under a hydrogen balloon. After 3 h, the reaction mixture was filtered through Celite and the Celite cake was washed with ethanol. The filtrate was concentrated to give of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid (3.9 g) as a white foam.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11]C)[CH:5]([NH2:9])[CH2:6][CH2:7]C)C.COC(OC)C(C#N)C>CO.[Ni]>[CH3:1][O:3][CH:4]([O:10][CH3:11])[CH:5]([NH2:9])[CH2:6][CH3:7]
Reactant: CCCC(N)C(OCC)OCC
Agent: [Ni]
Agent: COC(OC)C(C)C#N
Solvent: CO
Product: CCC(N)C(OC)OC
Reaction time: 0.06 h
Yield: 77.5 %

Procedure:
This reaction was run as for aminopentanal diethyl acetal [Example 15(c)(ii)] using MeOH as solvent (160 mL), 7.8 g of Raney nickel and 25 g (0.194 mol) of cyanopropionaldehyde dimethyl acetal. (H2 consumption 113% of theoretical after 3.5 hr.) The product after concentration at reduced pressure analyzed as an essentially pure single component at 3.40 min by gc (20 g, 77.5% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1.[CH2:23]([O:26][C:27]([N-:29][S:30]([NH2:33])(=[O:32])=[O:31])=[O:28])[CH:24]=[CH2:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[CH2:23]([O:26][C:27]([N:29]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)[S:30]([NH2:33])(=[O:32])=[O:31])=[O:28])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)[N-]S(N)(=O)=O
Reactant: OCc1csc2cncn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N(Cc1csc2cncn12)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.3 %

Procedure:
Under an argon atmosphere at -51° C., 0.71 ml of diethyl azodicarboxylate was added dropwise to 5 ml of an anhydrous tetrahydrofuran solution containing 463 mg of 3-hydroxymethylimidazo[5,1-b]thiazole, 811 mg of N-allyloxycarbonyl-N-aminosulfonylamide and 1180 mg of triphenylphosphine, and the mixture was then stirred at -51° C. to -37° C. for 15 minutes and further stirred for 70 minutes, while the solution was heated up to room temperature. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then dissolved in 50 ml of ethyl acetate. Further, the solution was extracted with 2N hydrochloric acid (30 ml×2), and the combined aqueous layer was then washed with 20 ml of ethyl acetate. After neutralized (pH 7) with sodium hydrogencarbonate, the neutralized solution was extracted with ethyl acetate (100 ml×2). The thus extracted organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 145.6 mg of the title compound in a milky white amorphous state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Li])CCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(O)(=O)C>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([B:22]3[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of commercially available 1-(4-fluorophenyl)-1H-pyrazole [CAS No 81329-32-0] (2.27 g, 14.0 mmol) in THF (100 ml) was added drop wise at −78° C. under argon atmosphere n-butyl lithium (1.6N in hexane, 10.5 ml, 16.8 mmol. The reaction mixture was allowed to stir for 1 h at −78° C. Afterwards commercially available 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.84 g, 3.12 ml, 15.0 mmol) was added drop wise at −78° C., and the mixture was stirred for 1.5 h at −78° C. The mixture was allowed to reach room temperature within 1 h, and acetic acid (0.925 g, 881 μl, 15.4 mmol) was added. The mixture was filtered using a Celite pad, which was washed with ethyl acetate, and the filtrate was evaporated to dryness. The crude product (4.36 g, light brown solid) was purified by flash chromatography on silica gel (heptane/ethyl acetate, 10-50%) to yield the title compound as an off-white solid (2.04 g, 51%), MS (ISP) m/z=289.5 [(M+H)+], mp 133° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH2:27]([S:30]([Cl:33])(=[O:32])=[O:31])[CH2:28][CH3:29].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[ClH:33].[NH2:16][C@H:15]([C:24](=[O:26])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:14][CH2:13][CH2:12][NH:11][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, 1-propanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[OH:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24](OCC)(=[O:26])C.CCCCCCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([CH2:17][OH:16])[CH2:19][CH2:20]3)=[O:26])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: OCC1CCNCC1
Reactant: Oc1ccc(Oc2ccc(Cl)cn2)cc1
Solvent: CCCCCCC
Product: O=C(Oc1ccc(Oc2ccc(Cl)cn2)cc1)N1CCC(CO)CC1

Procedure:
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and 4-hydroxymethyl-piperidine. The crude product was subjected to column chromatography (ethyl acetate/heptane, 1:1) (75%, colorless oil). HPLC-MS: m/z=363.1 (M+1); Rt: 3.58 min.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:10]>>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:10]
Reactant: N
Reactant: O=C(O)c1ccccc1
Product: O=C([O-])c1ccccc1
Product: [NH4+]

Procedure:
Benzoic acid in the form of a finely powdered solid was introduced as a continuous stream of particles into a polished stainless steel conically-shaped bowl of half-angle 5° and when the bowl was rotated at high speed (ca. 4000 rpm) the powder, under the influence of centrifugal forces, moved rapidly as a thin layer of material over the surface of the bowl and was flung from the rim. The rotating bowl was enclosed in a vessel into which ammonia gas was pumped and the benzoic acid powder moving on the surface of the bowl was contacted with ammonia gas. An exothermic reaction occurred and ammonium benzoate was formed almost quantitatively before the powder reached the rim. It is likely that reaction of ammonia with benzoic acid takes place initially at the surface of the benzoic acid particles and then the ammonium benzoate first formed becomes detached from the benzoic acid, thus exposing a new surface for further attack by ammonia. This process is probably aided by the abrasion of the particles moving over the surface of the reactor bowl. The ammonium benzoate product collected from the rim of the bowl was a noticeably finer powder than the benzoic acid reactant. The nature of the product was confirmed to be pure ammonium benzoate by IR and NMR spectoscopy.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]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=C1Cc2ccc(Br)cc2N1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1Cc2ccc(-c3cccs3)cc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and thiophene-2-boronic acid (4.38 g, 34.2 mmol) in three portions over 1.5 hours. The mixture was stirred at 100° C. in an oil bath for 12 hours. The mixture was then diluted with ethyl acetate (400 mL) and washed with saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give 2.53 g (42%) of 6-thiophen-2-yl-1,3-dihydro-indol-2-one a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH-:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][CH:3]=1.[O:11]=[C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:25](O)=O)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[F:9][C:6]1[C:7]2[N:8]=[C:25]([C:20]3[C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:11])[C:24]=4[CH:23]=[CH:22][CH:21]=3)[NH:1][C:2]=2[CH:3]=[CH:4][C:5]=1[F:10]
Reactant: [NH-]c1c(N)ccc(F)c1F
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2c(F)c(F)ccc2[nH]1
Temperature: 115 °C

Procedure:
The procedure used in Example 68 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, heat, at 115° C. for 6 hours, a suspension of 1.7 g of (6-amino-2,3-difluorophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 35 ml of acetic acid. After cooling, bring to dryness under reduced pressure. Take the residue up in water and bring to pH=8 by adding a 10% saturated aqueous solution of sodium hydrogen carbonate, with water. The precipitate that formed is filtered off, washed with water, and rinsed with diisopropyl ether. In this way, we obtain 1.5 g of 4-(4,5-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([NH:5][CH2:6][CH2:7]2)[CH2:3]1.F[C:11]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(#N)C.O>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:20]3[CH:21]=[CH:22][C:17]([C:15]([C:14]4[CH:23]=[CH:24][CH:11]=[CH:12][CH:13]=4)=[O:16])=[CH:18][CH:19]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C[C@H]2CCN(c3ccc(C(=O)c4ccccc4)cc3)[C@H]2C1
Temperature: 80 °C

Procedure:
The product of Example 7B (35 mg, 0.28 mmole), 4-fluorobenzophenone (110 mg, 0.55 mmole) and triethylamine (200 μl, 1.43 mmole) were dissolved in 1 ml of acetonitrile and heated at 80° C. under N2 for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography (eluting with a mixture of 5% methanol and 0.5% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.93 (d, J=8.82 Hz, 2H) 7.20-7.34 (m, 5H) 6.50 (d, J=9.16 Hz, 2H) 4.31-4.47 (m, 1H) 4.19 (s, 2H) 3.55-3.67 (m, 1H) 3.39-3.52 (m, 1H) 3.09-3.28 (m, 1H) 2.44-2.89 (m, 4H) 2.15-2.27 (m, 1H) 2.09 (s, 3H) 1.94-2.06 (m, 1H); MS (M+H)+=307.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>CC(O)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OC(C)=O)cc1
Solvent: CC(=O)O
Product: COc1ccc(OC(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 270 g. (1.62 m.) of p-methoxyphenyl acetate (part A) and 772 ml. of HOAc was added dropwise 77.5 ml. of fuming HNO3 maintaining a temperature of 5° to 10°C. Stirring was continued for 60 minutes at 5° to 10°C following the addition, then the solution was poured into 6 liters of ice. The orange semi-solid was collected by filtration and washed with cold water. The crude product was recrystallized from 1000 ml. of ethanol to give 61 g., m.p. 93°-97°C.