Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([CH:14](F)[CH2:15][CH:16]([F:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([CH:14]([N:38]3[CH2:37][CH2:36][C:35]([OH:41])([C:32]4[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=4)[CH2:40][CH2:39]3)[CH2:15][CH:16]([F:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)C(F)CC(N1CCC(O)(c2ccc(Cl)cc2)CC1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone (3.94 g), 4-(p-chlorophenyl)-4-hydroxypiperidine (2.24 g) and dimethylsulfoxide (30 ml) was stirred at room temperature for 14 hours. The mixture was poured into 300 ml of water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield γ,4-bis-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2-fluorobutyrophenone. M.P. 190° - 193°C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:22])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)C(=O)CN4)cc2)CC1
Yield: 38 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with 1-methyl piperazine as in General Procedure 8 to give the title compound as a light yellow solid (38% yield). m.p. 223° C. (dec), LCMS: m/z=478.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.35-2.48 (m, 4H), 3.48-3.54 (m, 2H), 3.70-3.80 (m, 2H), 4.34 (s, 2H), 5.11 (s, 1H), 5.22 (s, 2H), 6.90-6.98 (m, 2H), 7.06-7.13 (m, 1H), 7.20 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH:13]S(C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].[ClH:20]>CO.O1CCOCC1>[ClH:20].[CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1cnc(S(C)(=O)=O)s1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-thiazol-5-yl)-propyl]-amide (80 mg, 0.3 mmol) in methanol (5 mL) is added a 4 N solution of hydrochloric acid (1 mL, 4 mmol) in dioxane. After 1 hour, the mixture is concentrated and diluted with dichloromethane (2 mL) followed by hexanes (10 mL), and concentrated to afford (S)-1-(2-methanesulfonyl-thiazol-5-yl)-propylamine hydrochloride.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:41]=[CH:40][C:27]([CH2:28][N:29]([CH2:37][CH2:38][OH:39])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:41]=[CH:40][C:27]([CH2:28][N:29]([CH2:37][CH:38]=[O:39])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of Dess-Martin periodinane (0.51 g, 0.0012 mol) in anhydrous CH2Cl2 (10 mL) was added a solution of tert-butyl 4-chlorobenzyl(2-hydroxyethyl)carbamate (II-2) (0.29 g, 0.001 mol) in anhydrous CH2Cl2 (5 mL). Then the reaction mixture was stirred at room temperature for 21 h under N2 atmosphere. 1 M of Na2S2O3 (10 mL) was added to the reaction mixture, and after stirring 10 min, the reaction mixture was extracted with CH2Cl2 (10 mL×3). The combined organic layers were washed with 5% aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried over Na2SO4, and evaporated in vacuo. The residue was then purified by column chromatography (silica gel, Hexanes:EtoAc=8:2) to afford colorless oil (IV-1, 0.20 g, 72%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[CH3:16][N:17](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1)#[N:17]
Reactant: COC(=O)c1oc2ccc(Br)cc2c1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1oc2ccc(C#N)cc2c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (6.06 g) synthesized above, zinc cyanide (2.64 g) and N,N-dimethylformamide (60 mL) was added tetrakis(triphenylphosphine)palladium (0) (1.31 g), and the mixture was deaerated and stirred under argon atmosphere at 80° C. overnight. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (4.20 g, 87%) as a pale-brown solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Reactant: Cc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1

Procedure:
To a stirred solution of methyl 3-iodo-5-nitrobenzoate (7.76 g, 24 mmol) and p-tolylboronic acid (3.94 g, 28 mmol) in toluene (576 mL) was added cesium carbonate (9.4 g, 28 mmol) in water (7.8 mL). The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (860 mg, 0.74 mmol) was added at room temperature. The reaction mixture was heated to reflux for 3 days. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford a white solid.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:22]1([CH2:21][O:20][C:18]([NH:1][C@H:2]([C:15]([N:69]2[CH2:70][CH2:71][N:66]([C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)[CH2:67][CH2:68]2)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol) of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of dimethylformamide were added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml (0.268 mol) of DIEA with stirring and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate and aqueous saturated sodium hydrogen carbonate solution. The aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution. The organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 3% aqueous ammonia solution and twice with 100 ml of water. The organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[CH2:9][Br:10])[C:5](Cl)=[O:6].[NH2:17][CH:18]1[C:29](=[O:30])[N:20]2[CH:21]([C:26]([OH:28])=[O:27])[CH:22]([OH:25])[CH2:23][S:24][C@H:19]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[CH2:9][Br:10])[C:5]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[CH:21]([C:26]([OH:28])=[O:27])[CH:22]([OH:25])[CH2:23][S:24][C@H:19]12)=[O:6]
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 118.2 %

Procedure:
2-Methoxyimino-3,3-diethoxy-4-bromobutyryl chloride (syn isomer, 400.5 g) and 7-amino-3-hydroxycepham-4-carboxylic acid (230 g) were treated in a similar manner to that of Example 41 to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 621 g).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17]>ClCCl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:4]
Reactant: CC(C)CC(Br)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)CC(Br)C(=O)OC(C)(C)C
Temperature: -40 °C
Yield: 98 %

Procedure:
The product from Step 1 above (63.3 g, 0.32 mol) was dissolved in dichloromethane (250 mL), concentrated sulfuric acid (2 mL) was added, and cooled to −40° C. in a pressure bottle. Isobutene was condensed into the solution to roughly double the volume, and the mixture was then allowed to warm to room temperature overnight. Following evaporation to half of the volume under reduced pressure, the solution was washed with 10% aqueous sodium bicarbonate, dried over Na2SO4, and thoroughly evaporated under reduced pressure at room temperature to leave the title compound as a yellow oil (79.9 g, 0.314 mol; 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[C:13](F)=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1>CN(C=O)C.O>[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([F:21])=[CH:14][C:13]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A 0° C. mixture of 2-chloro-4-hydroxypyridine (817 mg, 6.30 mmol) in DMF (30 mL) was treated with NaH (60% in mineral oil, 277 mg, 6.93 mmol), stirred for 1 h, treated with 5-bromo-2,4-difluoronitrobenzene (1.50 g, 6.30 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16 g, 53%). MS (ESI) m/z: (M+H+): 348.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1)=[O:4].[CH2:11]([C:13]1[CH:56]=[CH:55][C:16]2[CH:17]([C:27]3[C:28](=[O:54])[NH:29][C:30](=[O:53])[N:31]([C:33]4[CH:38]=[CH:37][N:36]=[C:35](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:34]=4)[CH:32]=3)[C:18]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=3[CH:20]=[CH:21][C:15]=2[CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:56]=[CH:55][C:16]2[CH:17]([C:27]3[C:28](=[O:54])[NH:29][C:30](=[O:53])[N:31]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([NH:1][CH2:2][C:3]([NH:5][C:6]5[NH:10][N:9]=[N:8][N:7]=5)=[O:4])[N:34]=4)[CH:32]=3)[C:18]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=3[CH:20]=[CH:21][C:15]=2[CH:14]=1)[CH3:12]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Reactant: NCC(=O)Nc1nnn[nH]1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nnn[nH]3)n2)c(=O)[nH]c1=O

Procedure:
The title compound was prepared from the product of step (ii) and the product of example 15 step (viii) by the method of example 7 step (i).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6](O)=[O:7].COC1N=C(N)C=C(OC)[N:16]=1>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([NH2:16])=[O:7]
Reactant: COc1cc(N)nc(OC)n1
Reactant: CNc1cc(C(=O)O)ccc1O
Product: CNc1cc(C(N)=O)ccc1O
Yield: 67 %

Procedure:
Using 3-methylamino-4-hydroxylbenzoic acid and 2,6-dimethoxy-4-aminopyrimidine as materials, compound 3 is synthesized following a similar method as in Example 28. Yield: 67%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[C-]#N.[Na+].O>CN(C)C=O>[C:9]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)#[N:10]
Reactant: Brc1ccc(Br)nc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Br)cn1
Temperature: 150 °C
Reaction time: 7 h
Yield: 69.9 %

Procedure:
In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=O)C.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:3]
Reactant: NCCCCN
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Product: Cc1c2ccnc(C(=O)NCCCCN)c2cc2c3cc(O)ccc3n(C)c12

Procedure:
0.47 g (1.407 mmol) of the ester obtained in Step A of Example 11 are dissolved in 9 ml of 1,4-diaminobutane under an argon atmosphere. The mixture is heated at 130° for 3 hours.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[C:9]([C:10]#[N:11])=[CH:8][NH:7][N:6]=1.Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].O>CN(C=O)C>[C:10]([C:9]1[C:5]([C:4]([F:3])([F:12])[F:13])=[N:6][N:7]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[CH:8]=1)#[N:11]
Reactant: N#Cc1c[nH]nc1C(F)(F)F
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
NaH (60% [w/w] suspension in oil, 130 mg, 3.25 mmol) was added to a solution of 3-(trifluoromethyl)-4-cyanopyrazole (520 mg, 3.23 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 1 h before adding 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.023 g, 3.23 mmol). The reaction mixture was heated at 65° C. for 4 h then allowed to cool to RT. Water (20 mL) was added and the reaction mixture extracted with EtOAc (3×20 mL). The combined EtOAc layers were washed with water (5×20 mL), brine (20 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the crude reaction mixture as a cream solid. Purification by flash chromatography (eluent 1:1 EtOAc:heptane) gave desired product (626 mg, 1.58 mmol, 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][C:5]=1[NH2:6])([O-])=O.CO.C(=O)([O-])[O-].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][C:5]=1[NH2:6]
Reactant: COCCOc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCOc1ccc(N)c(N)c1

Procedure:
A mixture of 11 g. of 2-nitro-5-(2-methoxyethoxy) aniline, 220 ml. of methanol, 460 ml. of water, 40 g. sodium carbonate and 60 g. sodium hydrosulfite is refluxed for 15 minutes. The solution is concentrated, diluted with water and extracted with chloroform. Evaporation of the chloroform leaves 1,2-diamino-4-(2-methoxyethoxy) benzene as an oil, sufficiently pure for the next step.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].O>C(O)(=O)C>[CH3:1][S:2]([O:5][CH:6]1[CH2:17][C:10]2[C:11]([CH3:15])([CH3:16])[C:12](=[O:14])[O:13][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)OC2=C1CC(OS(C)(=O)=O)C=C2
Yield: 70 %

Procedure:
A solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (20 parts) in warm acetic acid (200 parts) was treated with 200 parts of a 20% aqueous solution of chromic oxide. After about 15 seconds the mixture was poured into water and the solution extracted with ether. The extracts were thoroughly washed with aqueous sodium bicarbonate, then dried and the solvent evaporated to give 2-oxo-2,5-dihydro-3,3-dimethyl-benzofuran-5-yl methanesulphonate (14 parts, 70% yield), melting point 120°-121° C. after recrystallisation from benzene-petroleum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([OH:28])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O[CH2:49][CH2:50][Cl:51])(=O)=O)=CC=1>>[Cl:51][CH2:50][CH2:49][O:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[C:12]#[N:13])[CH2:27]2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Product: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCCl)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 73 %

Procedure:
The procedure of Example of 32 is used with 0.45 g of α-(3,4-dimethoxyphenyl)-1,3-dihydro-5-hydroxy-6-methoxy-α-[(4-methylphenyl)thio]-2H-isoindole-2-heptanenitrile and 0.65 g of 2-chloroethyl p-toluenesulfonate. This affords 0.367 g of the desired product as a light brown oil. MS(Hi res): m/z Calcd for C33H39N2SClO4 595.2397 Found 595.2391(M+H)
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19](F)[C:18]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:16][C:17]1[C:18]([N+:25]([O-:27])=[O:26])=[C:19]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)cc(F)c2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxlate, 2,4,6-trifluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(3,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[O:15])=[C:12]([OH:11])[CH:20]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COc1ccc(C(=O)O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Yield: 84.6 %

Procedure:
A mixture of 3.96 g of 4-amino-1H-indole, 70 ml of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxy-benzoic acid and 6.2 g of dicyclohexylcarbodiimide was refluxed for 24 hours and was evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ethyl acetate and excess 4-amino-1H-indole was removed by washing with 2N hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in ether and dried at 50° C. to obtain 7.1 g of 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 190° C.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23]CC2C=CC=CC=2)[NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][OH:23])[NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11]1
Reactant: c1ccc(COCC2CNCC(COCc3ccccc3)NCCOCCN2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCC1CNCC(CO)NCCOCCN1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
5,9-Bis(benzyloxymethyl)-1-oxa-4,7,10-triazacyclododecane (0.24 g, 0.6 mmol) was dissolved in methanol (10 ml). Ammonium formate (0.20 g, 3 mmol) and 10% Palladium on carbon (0.40 g) were added and the mixture was stirred under a nitrogen atmosphere at 50° C. for 16 hours. The catalyst was filtered off and washed with methanol (5 ml). The filtrate was evaporated and the 5,9-Bis-(hydroxymethyl)-1-oxa-4,7,10-triazacyclododecane was isolated as a colourless oil. Yield 0.12 g (86%).