Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:35][CH2:36][CH3:37])[O:38][CH2:39][CH3:40])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 66 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH:21](Br)[CH2:22][CH3:23])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13].[SH:26][C:27]1[N:28]=[N:29]C=[CH:31][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(OCC)(=O)C.CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH:21]([S:26][C:27]2[NH:28][N:29]=[CH:31][N:32]=2)[CH2:22][CH3:23])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Reactant: Sc1nccnn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(Sc1ncn[nH]1)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 9A; 50 mg) is introduced into DMF (1 ml) and, after addition of 3-mercapto-1,2,4-triazine (15 mg) and cesium carbonate (78 mg), stirred at RT overnight. The reaction mixture is mixed with ethyl acetate (50 ml) and 0.5N hydrochloric acid (50 ml), the aqueous phase is extracted with ethyl acetate (twice 50 ml), and the combined organic phases are washed with saturated sodium chloride solution (twice 100 ml). The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator. The residue is purified on a preparative HPLC. 14 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=2)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.O>[C:16]([CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=2)[C:6]=1[C:4]([OH:5])=[O:3])([OH:18])=[O:17]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)n(-c2cccc(C(=O)OC)c2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-ethoxycarbonylmethyl-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid ethyl ester (1.31 g, 3.2 mmol) in THF-methanol (2:1, 25 mL) was added a solution of NaOH (0.64 g, 16.0 mmol) in H2O (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with H2O (50 mL) and washed with diethyl ether (50 mL). The aqueous layer was acidified with concentrated HCl to pH=1. The white precipitated was filtered off and dried in vacuo to afford 1.08 g of white solid (quantitative yield): 1H NMR (DMSO-d6) δ 4.13 (s, 2H), 7.05 (d, 1H), 7.21 (t, 1H), 7.31 (t, 1H), 7.62–7.71 (m, 2H), 7.76–7.82 (m, 2H), 8.01–8.05 (m, 1H); 13C NMR (DMSO-d6) 31.0, 111.1, 119.0, 121.2, 121.4, 126.2, 127.4, 127.8, 128.3, 128.7, 129.9, 132.2, 138.9, 139.3, 162.6, 167.0, 172.5. Anal: Calcd for C18H13NO6: C, 63.72; H, 3.86; N, 4.13. Found: C, 63.32; H, 4.08; N, 3.97.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25](Cl)=[O:26])[CH2:13]2)[CH3:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[CH2:37][CH2:36]1>C(Cl)Cl>[C:41]([CH:38]1[CH2:39][CH2:40][N:35]([C:25]([N:14]2[CH2:15][CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH:12]([CH:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH3:11])[CH2:13]2)=[O:26])[CH2:36][CH2:37]1)#[N:42]
Reactant: N#CC1CCNCC1
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)N2CCC(C#N)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of (3RS,4SR)-3-[(SR)-1-(5-Cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (30 mg, 0.070 mmol) in CH2Cl2 (4 mL) were added Et3N (0.015 mL, 0.11 mmol) and piperidine-4-carbonitrile (commercially available) (9 mg, 0.084 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 24 mg (69%) the title compound as light yellow oil. ES-MS m/e: 498.0 (M+H+).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C1(C)C=CC=CC=1>[Br-:20].[C:24]([CH2:23][CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)#[N:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#CCCCBr
Solvent: Cc1ccccc1
Product: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 50.6 %

Procedure:
Triphenylphosphine (1.4789 g) was dissolved in anhydrous toluene (44.4 ml) and then added with 4-bromo-butyronitrile (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (834.7 mg), followed by thermal reflux for 22 hours. After the reaction, a precipitated product was filtrated. The precipitate obtained through filtration was washed with toluene and thermally dried under reduced pressure, thereby obtaining the subject compound (1.1697 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:8][C:9]3[C:10]([N:24]=2)=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=2[CH:17]=3)=[N:4][NH:5][CH:6]=1.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:18]([N:15]1[C:16]2[CH:17]=[C:9]3[NH:8][C:7]([C:3]4[C:2]([NH:1][C:31]([N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[O:32])=[CH:6][NH:5][N:4]=4)=[N:24][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:23])[C:14]1=[O:21])([CH3:19])[CH3:20]
Reactant: O=C(Cl)N1CCCCC1
Reactant: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4NC(=O)N4CCCCC4)[nH]c3cc21

Procedure:
Piperidine-1-carboxylic acid[3-(5-isopropyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-isopropyl-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one (200 mg, 0.247 mmol) and piperidine-1-carbonyl chloride (40.0 mg, 0.271 mmol). 40 mg (37%) %) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CCCCCC.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:24]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccccc2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-5-methoxybenzoic acid (5 g, 21.6 mmol) in 50 mL of THF is stirred under argon at −78° C., and a 1.6 M solution of n-butyllithium in hexane (29 mL, 45 mmol) is then added dropwise. The reaction mixture is stirred for 1 hour at −78° C. and benzoyl chloride (3.2 g, 22.7 mmol) is then added dropwise. The reaction mixture is stirred for 1 hour 30 minutes at −78° C. and then for 18 hours at room temperature. The mixture is hydrolysed with 100 mL water and then washed with ethyl acetate. The aqueous phase is acidified by addition of 5 N hydrochloric acid and then extracted with ethyl acetate. The organic phase obtained is washed with brine and then dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure, 5.4 g of a colourless oil are obtained, and are used without purification.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[C:9]([F:17])[CH:8]=1.O=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1>[F:17][C:9]1[CH:8]=[C:7]([C:19]2[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22][CH:23]=2)[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=1
Reactant: Fc1cc(Br)c2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)cc2c1OCCO2
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of isopropyl magnesium chloride in THF (2M, 5.39 mL, 10.78 mmol) was added to a solution of 5-bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Int-53) (1 g, 4.31 mmol) in THF (10 mL) at −45° C. drop-wise and then allowed it to warm up to 5° C. over a period of 1 h. The reaction mixture was cooled again to −45° C. and a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.6 g, 8.62 mmol) in THF (10 mL) was added drop-wise maintaining the temperature at −45° C. The reaction mixture was warmed to 25° C. and stirred for 1 h and then quenched with saturated NH4Cl solution (100 mL). The reaction mixture was extracted with ethyl acetate (3×30 mL) and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure and purified by column chromatography (using silica gel and 20% ethyl acetate Hexane as eluent) to afford tert-butyl 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (Int-54). MS (ESI) m/z 340 (M−+1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:62][N:61]([C:63](=[O:65])[CH3:64])[CH2:60]1>>[C:63]([N:61]1[CH2:62][CH:59]([NH:58][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:60]1)(=[O:65])[CH3:64]
Reactant: CC(=O)N1CC(N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C(C)=O)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(3-aminoazetidin-1-yl)ethanone. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=12.4 Hz, 1H) 1.34-1.45 (bq, 2H) 1.57-1.68 (m, 3H) 1.78 (s, 3H) 1.84 (m, 3H) 3.32 (s, 3H) 3.88 (m, 1H) 3.95 (s, 3H) 4.03-4.12 (m, 4H) 4.42 (t, J=8.2 Hz, 1H) 4.45-4.51 (m, 1H) 4.68 (q, J=6.8 Hz, 3H) 7.51 (dd, J=8.3, 1.8 Hz, 1H) 7.54 (d, J=1.5 Hz, 1H) 7.93 (s, 1H) 8.22 (s, 1H) 8.30 (d, J=8.3 Hz, 1H) 8.89 (d, J=6.8 Hz, 1H). [M+H] calc'd for C27H33F2N7O4 558. found 558.
Reaction SMILES: ClC1C=CC(C([O:8][C@H:9]2[C@:13]([F:15])([CH3:14])[C@H:12]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][C:19]([NH2:26])=[N:20][C:21]=4Cl)[O:11][C@@H:10]2[CH2:27][O:28]C(=O)C2C=CC(Cl)=CC=2)=O)=CC=1.[Na].[CH3:41][O-:42].Cl>CO.ClCCl>[NH2:26][C:19]1[N:18]=[C:17]2[C:22]([N:23]=[CH:24][N:16]2[C@@H:12]2[O:11][C@H:10]([CH2:27][OH:28])[C@@H:9]([OH:8])[C@:13]2([F:15])[CH3:14])=[C:21]([O:42][CH3:41])[N:20]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: C[O-]
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 25 °C

Procedure:
To a dry 5 L three-necked round flask fitted with a mechanical stirrer and an addition funnel was loaded (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (6b, 313.2 g, 526.5 mmol). The solid was suspended in anhydrous methanol (2.1 L) and cooled in an ice-water bath under an atmosphere of nitrogen. A solution of sodium 25 wt. % methoxide in methanol (361 mL, 1.58 mol) was added via an additional funnel over 20 min to give a clear solution. The reaction was allowed to warm to room temperature for 6 hours to form a turbid solution. The completion of the reaction was confirmed by LC/MS by the lack of any remaining 6-chloro deprotected nucleoside. The reaction solution was acidified with con. HCl (132 mL, 1.58 mol). After standing at room temperature (1 h), the solution was filtered to remove a white precipitate. The precipitate was washed with methanol (3×50 mL). The combined filtrate was concentrated under reduced pressure to afford a sticky solid residue. The residue was mixed with 420 mL of 2 N HCl (420 mL) and dichloromethane (1 L). The organic layer was separated and the aqueous layer was extracted with additional dichloromethane (3×500 mL). To the aqueous layer, ethyl acetate (1.4 L) was added and solid sodium carbonate (86 g) was added portion-wise to neutralize the aqueous layer to ca pH 8 (caution: foaming). After separation of the organic layer, the solid in aqueous layer was dissolved by adding more water (200 mL). The aqueous layer was extracted with ethyl acetate (3×700 mL and 400 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to a light yellow color solid that was redissolved in acetone (820 mL) at 50° C. and stirred until new solid formation initiated. The saturated solution was cooled in a freezer and product was collected by filtration. The white solid was rinsed with acetone (2×150 mL) and ethyl ether (3×80 mL) and dried (0.2 mm Hg, 50° C., 4H) to a white crystalline solid, 151.6 g (92%) of material with NMR and HPLC matching material purified by chromatography.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21](C(C)=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:27]C(C)([O-])C.[K+].Cl[CH2:34][Cl:35]>C(O)(C)(C)C>[Cl:35][C:34]#[C:27][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:17][CH2:16]1
Reactant: CC(C)(C)[O-]
Reactant: ClCCl
Reactant: CCCCCC1CCC(c2ccc(C(C)=O)cc2)CC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCC[C@H]1CC[C@H](c2ccccc2C#CCl)CC1

Procedure:
312.3 g (1.5 mol) of phosphorus pentachloride are added carefully to a solution of 172.4 g (1.0 mol) of methyl 4-(4-pentylcyclohexyl)phenyl ketone in 1.4 l of dichloromethane. The mixture is refluxed for 3 days and then poured onto ice; the organic phase is separated off, and the aqueous phase is extracted once with dichloromethane. The combined organic phases are evaporated on a rotary evaporator, and the residue, together with 263.2 g (2.34 mol) of potassium t-butoxide, is dissolved in 1.4 l of t-butanol. The mixture is refluxed for 15 hours and then evaporated on a rotary evaporator. The residue obtained is chromatographed on a silica gel column using petroleum ether as eluent. The eluate is evaporated on a rotary evaporator, and the product is recrystallized from petroleum ether (crystallization at -70° C.) and from 2-propanol. C 66N 70 I, η (20° C.) 13 mm2 /sec, Δn 0.208, Δε +6.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=1[NH:19]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=1[NH2:19]
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
tert-Butyl N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]carbamate (Intermediate 15, 1.4 g, 3.82 mmol) was dissolved in CH2Cl2 (20 mL) and TFA (5 mL) was then added. The mixture was stirred for 2 h at r.t. and was then concentrated in vacuo. The resulting residue was dissolved in CH3OH, absorbed onto an SCX column, washed with CH3OH and eluted with methanolic ammonia. The fractions that contained product were combined and concentrated. Purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (0.6 g, 59%) as an orange oil which crystallised on standing; 1H NMR: 2.22 (3H, s), 2.39-2.47 (4H, m), 2.87-2.97 (4H, m), 3.88 (3H, s), 4.99 (2H, s), 6.72 (1H, s), 7.20 (1H, s); m/z: ES+ MH+ 267.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperazine (1.38 g, 7.41 mmol) in acetonitrile (10 mL) was stirred with triethylamine (2.07 mL, 14.8 mmol) and methyl 2-bromoacetate (1.02 mL, 11.1 mmol) at room temperature for 4 hours and then filtered. The filtrate was concentrated, and after addition of saturated aqueous ammonium chloride, extracted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 83%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Br)cc1F
Temperature: 90 °C
Yield: 91 %

Procedure:
A total of 2075 g (8.79 moles) of crude 4-bromo-2,5-difluorobenzoic acid from step (b) was treated with thionyl chloride (2.0 L), and the resulting slurry was slowly heated to reflux (90° C. internal) to obtain a solution. After removal of excess thionyl chloride, the product was collected at 85°-95° C. (oil pump, vacuum not measured), leaving a solid residue. The distillate afforded 2045 g (91%) of a liquid which was used directly in the next step.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.C(OP(Cl)(OCC)=O)C.[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1.CCCCCC.O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7](/[CH:10]=[CH:33]/[C:32]2[CH:35]=[CH:36][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To 15 g (85.47 mmol) of methyl p-tolyl sulfone dissolved in 450 cm3 of tetrahydrofuran are added, at a temperature in the region of 0° C. under an argon atmosphere, 117.5 cm3 (188 mmol) of a 1.06 M solution of n-butyl-lithium in hexane. After stirring for 30 minutes at a temperature in the region of 0° C. are added, under an argon atmosphere, 13 cm3 (85.47 mmol) of diethylchlorophosphate dissolved in 70 cm3 of tetrahydrofuran. After stirring for 30 minutes at a temperature in the region of 0° C., the reaction mixture is cooled to a temperature in the region of −78° C., followed by addition, under an argon atmosphere, of 13.05 g (85.47 mmol) of 4-nitrobenzaldehyde dissolved in 130 cm3 of tetrahydrofuran. After stirring for 1 hour at a temperature in the region of −78° C., the temperature of the reaction mixture is allowed to rise to a temperature in the region of 20° C., 100 cm3 of water are added and the mixture is concentrated under reduced pressure (2.7 kPa) to give a beige-coloured solid. The solid is stirred in 250 cm3 of water for 20 minutes, filtered, washed with three times 40 cm3 of water and oven-dried under reduced pressure (2.7 kPa) at 35° C. for 5 hours to give 25.43 g of 1-[(E)-2-(4-methylphenyl)sulfonylvinyl]-4-nitrobenzene in the form of a beige-coloured solid melting at 176° C.; M.W.=303, IE: m/z=303 M+, m/z=239 [M-SO2]+, m/z=139 [CH3-Ph-SO]+.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].[Br:22]Br.II>O>[Br:22][CH2:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][C:9]1[CH:17]=[CH:18][CH:19]=[C:7]([C:6]([F:20])([F:21])[F:5])[CH:8]=1)=[O:16]
Reactant: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A one-liter reaction flask equipped with a mechanical stirrer, air-cooled condenser, thermometer and dropping funnel was charged with 290 ml of acetic acid and 167.3 g (0.68 mole) of 3'-trifluoromethylacetoacetanilide. Only a portion of the latter dissolved. The dropping funnel contained 108.8 g (0.68 mole) of bromine, a crystal of iodine and 65 ml of acetic acid. The pot mixture was stirred as the bromine solution was added dropwise while maintaining the reaction temperature at 20°-25°. The reaction solids appeared to dissolve and reprecipitate as the bromine addition was continued. When about 65% of the bromine solution had been added, a clear reaction solution was obtained. All material remained in solution when the remaining quantity of bromine solution was added. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning, the solidified mass was added to 2.8 liters of cold water and stirred. The white solid was collected on a vacuum filter and the filter cake was washed with an additional one liter of water. After drying, there was obtained 210 g (95%) of 4-bromo-3'-trifluoromethylacetoacetanilide, m.p. 66°-8°. N.M.R. (CDCl3) ##STR3## 5.3 (CH, enol), 7.2-7.8 (aromatic), 9.0 (HNC=O).