Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([Br:27])C(=O)C1>C1COCC1>[Br:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: Cn1nccc1C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(1-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylate (680 mg, 2.50 mmol) in THF (20 mL) was added NBS (486 mg, 2.80 mmol). The reaction mixture was stirred for 2 h. After concentration, the residue was purified by silica gel chromatography eluting with a 0-50% gradient of EtOAc in petroleum ether to give tert-butyl
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[CH:16]=2)[NH:11][N:10]=1)=[O:7].CCN(C(C)C)C(C)C.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>C(O)C.O>[F:26][C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([F:27])[CH:23]=1)[CH2:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:8][C:6](=[O:7])[C:5]1[CH:28]=[CH:29][CH:30]=[C:3]([CH2:2][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:4]=1
Reactant: C1CCNCC1
Reactant: O=C(Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12)c1cccc(CCl)c1
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12)c1cccc(CN2CCCCC2)c1
Yield: 66.3 %

Procedure:
3-Chloromethyl-N-[5-(3,5-difluoro-benzyloxy)-1H-indazol-3-yl]-benzamide (100 mg, 0.2342 mmol) in absolute ethanol (2.5 mL) was treated with DIPEA (0.12 mL, 0.7026 mmol) and piperidine (0.069 mL, 0.7026 mmol) and heated to reflux temperature. After 1 hour the reaction mixture was diluted with water, filtered with suction and dried at 50° C. under vacuum. Purification by flash chromatography over silica gel (eluent: DCM:MeOH:7N NH3 in MeOH 95:5:0.5) afforded 74 mg of title compound in 66% yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14]N1C(=O)CCC1=O.O>C(O)(=O)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (1 g, 5.5 mmol) in acetic acid (5 mL) at room temperature was added N-chlorosuccinimide (0.953 g, 7.14 mmol). The reaction was sealed and heated via microwave for 2 h at 80° C. The resulting mixture was poured into water (ca. 20 mL), cooled to 0° C., and the product collected by filtration. 1H-NMR (2:1 CDCl3/CD3OD, 500 MHz) δ 8.24 (d, J=2.7 Hz, 1H), 8.14 (d, J=2.8 Hz, 1H); 13C NMR (126 MHz, 2:1 CDCl3/CD3OD) δ ppm 167.8, 145.7, 139.6, 132.8, 130.9, 118.5, 116.1. Mass spec.: 215.18 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[F:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:9]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10][C:8]=2[CH:7]=[CH:6][C:5]=1[F:19])=[O:20]
Reactant: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1F
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(F)ccc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 5-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][NH2:14]>>[CH3:13][NH:14][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CN
Product: CNC(=O)c1ccc2[nH]cnc2c1
Yield: 67 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid and aqueous methylamine furnished the product in 67% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C[C@@H]1CNCCN1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2cc(C(F)(F)F)ccn2)CCN1
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a solution of (R)-2-methyl piperazine (4.0 g, 40 mmol) in xylene (100 mL) at 140° C. under nitrogen was added 2-chloro-4-trifluoromethylpyridine (7.26 g, 40.0 mmol) slowly over a period of 30 min. The heating was continued for additional 12 h and cooled. The reaction mixture was evaporated to a residue and the residue was purified by chromatography using chloroform/methanol (8/2) as eluent to afford of the title compound as a liquid (3.5 g, 36%). TLC—Chloroform/MeOH (8/2); Rf: 0.25.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:27]([F:28])([F:29])[F:30])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:12][CH2:13][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:19])[CH2:15][CH2:16]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Reactant: C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N2CCCCC2)(c2ccc(Cl)cc2)CC1

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 13 μL of piperidine (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL NMP. The resultant mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-(piperidine-1-carbonyl)-piperidin-1-yl]-ethanone:MS (ES) M+H expected=531.4, found=531.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Oc1ccc2sc(S(N)(=O)=O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (6.9 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (100 mg.) in dimethylformamide (30 ml.) is added lauroyl chloride (7 ml.) during a 1/2 hour period. The reaction mixture is stirred for 2 hours at room temperature, poured into ice water and hydrochloric acid, extracted into ether, washed with water, ammonium hydroxide (3 ml. diluted with water) dilute hydrochloric acid and dried over magnesium sulfate. The ether is evaporated at reduced pressure to give 2-sulfamoyl-5-benzothiazolyl dodecanoate.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[Na].[F:20][C:21]([C:24]1[NH:28][N:27]=[N:26][N:25]=1)([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:3]([CH2:2][N:26]2[N:27]=[N:28][C:24]([C:21]([F:23])([F:22])[F:20])=[N:25]2)[S:4][C:5]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1sc(CBr)nc1-c1ccccc1Cl
Reactant: FC(F)(F)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC#N
Product: COC(=O)c1sc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
5.00 g (14.4 mmol) of methyl 2-(bromomethyl)-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate were added to a solution of 10.00 g (18.7 mmol) of trifluoromethyltetrazole sodium salt in 100 ml of acetonitrile. Then 600 mg (4.32 mmol) of potassium carbonate were added to the reaction solution, and the mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. 10 ml of water were added to the residue and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography. (logP: 3.60; MH+: 404; 1H-NMR (400 MHz, DMSO, ppm): 3.71 (s, 3H), 6.70 (s, 2H), 7.40-7.60 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18]3=[C:21]([C:24]([O:26]CC)=O)[NH:22][N:23]=[C:17]3[CH2:16]2)=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:29]>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18]3=[C:21]([C:24]([NH2:29])=[O:26])[NH:22][N:23]=[C:17]3[CH2:16]2)=[N:13][CH:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1[nH]nc2c1CCN(c1ccc(NC(=O)OC(C)(C)C)cn1)C2
Reactant: N
Product: CC(C)(C)OC(=O)Nc1ccc(N2CCc3c(n[nH]c3C(N)=O)C2)nc1

Procedure:
The ethyl ester of ethyl 6-(5-tert-butoxycarbonylaminopyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylate is converted to carboxamide by amidation using a solution of aqueous ammonia, and results in the obtaining of 6-(5-tert-butoxycarbonylaminopyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxamide.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32]C(=O)OCC5C=CC=CC=5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:43][CH3:44])[N:8]=[CH:7][C:6]=2[N:5]([CH3:45])[C:4]1=[O:46])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:32][CH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:9]3[N:8]=[CH:7][C:6]4[N:5]([CH3:45])[C:4](=[O:46])[C@@H:3]([CH2:1][CH3:2])[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]=4[N:10]=3)=[C:18]([O:43][CH3:44])[CH:19]=2)[CH2:24][CH2:25]1
Reactant: [H][H]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(N4CCN(CCCNC(=O)OCc5ccccc5)CC4)cc3OC)nc2N1C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(N4CCN(CCCN)CC4)cc3OC)nc2N1C(C)C
Temperature: 20 °C
Reaction time: 24 h

Procedure:
33 mg (0.045 mmol) benzyl (3-{4-[4-((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-3-methoxy-phenyl]-piperazin-1-yl}-propyl)-carbamate are taken up in 5 ml of methanol combined with 4 mg palladium hydroxide and stirred for 24 h at 20° C. and 7 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27]Br)[CH:20]=1.CO>C1COCC1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][CH2:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])[CH:20]=1
Reactant: Cc1sccc1C(=O)O
Reactant: COc1ccc(Br)cc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Br)cc1CCc1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 2-methyl-thiophene-3-carboxylic acid (8.01 g, 56.0 mmol, 1.0 equiv) in THF (56 mL) at −78° C. was added a solution of lithium diisopropylamide (LDA; 2M, 56 mL, 112.0 mmol, 2 equiv). The orange solution was allowed to stir for 1 hr and then a solution of 4-bromo-2-bromomethyl-1-methoxybenzene (17 g, 73 mmol, 1.3 equiv) in THF (50 mL) was added dropwise via cannula. The solution was allowed to stir at −78° C. for one hour and then warmed to room temperature. The reaction was quenched by the addition of water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. Addition of methanol caused precipitation of a white solid, which was filtered and dried to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophene-3-carboxylic acid (5.3 g, 15.5 mmol, 27%). 1H NMR (300 MHz, d6-DMSO) δ 12.59 (s, 1H), 7.31 (dd, J=8.7, 5.7 Hz, 1H), 7.26 (dd, J=6.6, 5.4 Hz, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.27-3.35 (m, 2H), and 2.79-2.88 (m, 2H). LCMS ES− 339 (M−1), 341 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[NH:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].N12CCCNC1=NCCC2>C(Cl)Cl>[CH2:1]([N:8]1[C:9](=[O:14])[N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=c1[nH][nH]c(=O)n1Cc1ccccc1
Agent: C1CN=C2NCCCN2C1
Solvent: ClCCl
Product: O=c1[nH]n(Cc2ccc([N+](=O)[O-])cc2)c(=O)n1Cc1ccccc1
Yield: 58.6 %

Procedure:
A mixture of 4-benzylurazole (3.8 g, JCS Perkin II, 1975, 1325), p-nitrobenzyl bromide (4.3 g, Aldrich) and polymer-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (P-TBD, 6.3 g, Fluka) in DCM (400 ml) was refluxed under N2 for 24 hours. The P-TBD was filtered off and the filtrate evaporated to leave a gum which was flash chromatographed through a silica column using chloroform/methanol (19:1 v/v) to give the desired product as a solid (3.8 g).
Reaction SMILES: [NH4+].[Cl-].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1>O.[Fe]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH:5]=1)[NH2:11]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 91.7 %

Procedure:
The mixture of Fe powder (9.31 g, 167 mmol) and NH4Cl (2.48 g, 46.3 mmol) in water (50 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-2-nitrotoluene (10 g, 46.3 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3×100 mL). The organic solution was washed with H2O (3×200 mL) and brine (200 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 7.9 g (92%) of title compound as a pale yellow oil. 1H nuclear magnetic resonance (NMR) (CDCl3): 300 MHz δ 6.88 (m, 1H), 6.81 (m, 2H), 3.63 (bs, 2H), 2.09 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][C:52]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=4)=[O:53])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[CH2:46][CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 ml of trifluoroacetic acid and 0.36 ml of trifluoromethanesulfonic acid were added to a solution of 1.47 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-homopiperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 12) in 2.2 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was treated by a procedure similar to that described in Example 13(1), to give 1.8 g of the title compound as a powder.
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]2[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=2[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]2[CH2:22][CH2:23][C:24](=[O:26])[O:25][C:20]=2[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc2ccc(=O)oc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(C)CCOc1ccc2c(c1)OC(=O)CC2
Yield: 83.2 %

Procedure:
7-[2-(N-Dodecyl-N-methylamino)ethoxy]-2H-1-benzopyran-2-one (5.62 g, 14.5 mmol) in ethyl acetate was hydrogenated over palladium on activated carbon uder 30 psi and afforded the title compound (4.7 g, 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:35][CH3:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1.[NH2:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46])[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:35][CH3:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: CCOC(=O)CCN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CCC(=O)OCC)cc1OC
Yield: 28.9 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (2.7 g) (S)-3-aminohexan-1-ol (1.6 g). The sub-title compound (670 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.93 (1H, s), 6.86 (1H, d), 6.76 (1H, d), 4.80-4.65 (3H, m), 4.09 (2H, q), 3.88 (3H, s), 3.65 (2H, s), 3.50 (2H, s), 3.42-3.37 (1H, m), 3.24 (1H, ddd), 2.77 (2H, t), 2.46-2.41 (4H, m), 2.02 (3H, s), 1.82-1.72 (1H, m), 1.42-1.29 (1H, m), 1.26-1.19 (5H, m), 1.07-0.96 (5H, m), 0.74 (3H, t).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:7]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:13][CH2:14][CH2:15][CH:4]2[NH:3]1.[C:17](OCCl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>C(#N)C>[C:17]([O:12][C:9]1[CH:10]=[CH:11][C:6]2[N:5]3[CH2:13][CH2:14][CH2:15][CH:4]3[NH:3][S:2](=[O:1])(=[O:16])[C:7]=2[CH:8]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Reactant: CC(C)(C)C(=O)OCCl
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Solvent: CC#N
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)S(=O)(=O)NC1CCCN21

Procedure:
1.66 mmol of the compound of Example 1 in 40 ml of acetonitrile are stirred overnight at room temperature in the presence of 3.33 mmol of chloromethyl pivalate and a catalytic amount of dicyclohexyl-18-crown-6. The suspension is filtered and the filtrate is evaporated to dryness. The residue is taken up in dichloromethane and the organic phase is washed with a 1N hydrochloric acid solution and then with an aqueous saturated sodium chloride solution. After drying and evaporation, the resulting oily residue is crystallised from a mixture of ether/cyclohexane to yield the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.C([O-])([O-])=O.[Cs+].[Cs+].[O:41]1[C:43]2([CH2:48][CH2:47][S:46][CH2:45][CH2:44]2)[CH2:42]1.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([O:33][CH2:42][C:43]3([OH:41])[CH2:48][CH2:47][S:46][CH2:45][CH2:44]3)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: C1CC2(CCS1)CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (100 mg) in N,N-dimethylformamide (2 mL) is added Cs2CO3 (106 mg) and 1-oxa-6-thiaspiro[2.5]octane (37 mg). The mixture is stirred for 12 hour at 100° C. The mixture is diluted with water, acidified with 1 M aqueous HCl solution and extracted twice with ethyl acetate. The combined organic phases are washed with water and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 80:20:0→0:80:20) to give the title compound. Yield: 31 mg; LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=579 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:6]2[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:5]2[CH2:4][CH2:3][N:2]1[C:14](=[O:16])[CH3:15].S(Cl)(Cl)=O.[Cl:21][S:22](O)(=[O:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>>[C:14]([N:2]1[CH2:3][CH2:4][CH:5]2[C:9]3[CH:10]=[C:11]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:12]=[CH:13][C:8]=3[O:7][CH:6]2[CH2:1]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCC2c3ccccc3OC2C1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCC2c3cc(S(=O)(=O)Cl)ccc3OC2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (825 mg, 3.8 mmol) and thionyl chloride at 0° C., was added dropwise chlorosulfonic acid (1.25 g). The reaction mixture was stirred for 5 min at 0° C., for 2 h at r.t. and poured tehn into ice/H2O (75 g). The solution was brought to pH 7 by adding sodium carbonate and extracted with 75 mL ethyl acetate (2×). The combined organic layers were washed with H2O (2×), separated, and the solvent was evaporated. The resulting sulfonyl chloride was used in the next reaction step without further purification.