Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([NH2:18])[CH3:17])[CH:11]=2)=[CH:6][CH:5]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36](O)=[O:37])(=[O:30])=[O:29])=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>CO.CN(C=O)C>[F:2][C:3]([F:19])([F:20])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([NH:18][C:36]([C@@H:32]3[CH2:33][CH2:34][CH2:35][N:31]3[S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])=[O:37])[CH3:17])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: C[C@H](N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 12 h
Yield: 53.8 %

Procedure:
A mixture of (5)-1-(4′-trifluoromethyl-biphenyl-3-yl)ethylamine hydrochloride (75 mg, 0.25 mmol), (S)-1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (68 mg, 0.25 mmol), N-(3-dimethylamniopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (50 mg, 0.37 mmol) and DMF (2 mL) was added Et3N (0.10 mL, 0.75 mmol). After 12 h, MeOH (0.5 mL) was added to the reaction mixture and resulting solution was purified by preparative reverse-phase HPLC to afford (70 mg, 54%) of a white solid. MS (ESI): mass calcd. for C26H24F4N2O3S, 520.1; m/z found, 521.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.93-7.87 (m, 2H), 7.79 (d, J=8.0, 2H), 7.73-7.66 (m, 3H), 7.54 (d, J=7.6, 1H), 7.49 (t, J=7.6, 1H), 7.44 (d, J=7.6, 1H), 7.35 (d, J=8.0, 1H), 7.30-7.23 (m, J=8.7, 1H), 5.27-5.11 (m, 1H), 4.11 (dd, J=8.9, 3.1, 1H), 3.71-3.60 (m, 1H), 3.26-3.15 (m, 1H), 2.28-2.17 (m, 1H), 1.91-1.75 (m, 1H), 1.74-1.64 (m, 2H), 1.60 (d, J=7.0, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:22][CH2:21][C:15]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[CH:27]([C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)[OH:28]>>[F:25][C:26]([F:36])([F:37])[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([N:18]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:22][N:12]([S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:23])[F:24])(=[O:11])=[O:10])[CH2:13][CH2:14]3)[C:19]2=[O:20])=[CH:31][CH:30]=1)[OH:28]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2

Procedure:
This material was prepared in analogy to example 162 B) from 8-(2-trifluoromethyl-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. White solid. MS (ESI): 537.12 MH+).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]2[NH:12][N:1]=[N:13][C:8]=2[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of sodium nitrite (284 mg, 4.12 mmol) in water (1 mL) was added to a solution of 4-fluoro-benzene-1,2-diamine (520 mg, 4.12 mmol) in acetic acid (0.50 mL) and water (2.50 mL) at 0° C. The reaction mixture was stirred for few minutes at 50° C. and 1 hour at 0° C. The precipitate was filtered, washed with cold water and dried to yield 5-fluoro-1H-benzo[d][1,2,3]triazole (565 mg, 3.50 mmol, 85%).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([N:16]3[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:17]3)[C:4]=2[CH:3]=1.C=O.[CH2:32](Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([N:16]3[CH2:21][CH2:20][N:19]([CH3:32])[C@@H:18]([CH2:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:17]3)[C:4]=2[CH:3]=1
Reactant: ClCCl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccnc2)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Combine 2-methyl-10-((S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene (728 mg, 1.80 mmol) and formaldehyde (158 μL, 1.98 mmol, 37% in water), and methylene chloride (30 mL). Stir 10 minutes at ambient temperature. Add sodium triacetoxyborohydride (573 mg, 2.70 mmol) and stir 1 hour at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0%–4%) as the eluent to give the title compound (595 mg, 79%): Mass spectrum (ion spray): m/z=418 (M+1), 416 (M−1). Analysis calculated for C24H27N5S: C, 69.03; H, 6.52; N, 16.77. Found: C, 68.92; H, 6.60; N, 16.65.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:27][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[CH:21]=[CH:22][C:23]=1[Cl:28]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(Cl)c(Cl)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(Cl)c(Cl)c3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 3,4-dichlorophenyl borate (0.54 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 18 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2→1:1) to give pale yellow crystals of methyl 7-(3,4-dichlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (631.3 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:30][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 2-{3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}ethanol (0.30 g, 0.75 mmol) in methylene chloride (4.8 mL) was added slowly a solution of boron tribromide in methylene chloride (2.2 mL, 2.2 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight and the reaction was not complete. Thus additional 2 molar equivalents of BBr3 (1.5 mL, 1.5 mmol, 1.0M) were added, and the reaction mixture was stirred at rt for one more day and then the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution). The organic solvent was removed under vacuum and water/EtOAc was added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (222 mg, 65%). LCMS for C20H21BrClN4O (M+H)+: m/z=447.0, 449.0. 1H NMR (400 MHz, CD3OD): δ 7.92 (s, 1H), 7.37 (m, 3H), 7.20 (d, J=7.6 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.58 (m, 3H), 3.74 (t, J=7.6 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([Si:30]([CH3:47])([CH3:46])[O:31][C@H:32]1[C@H:37]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([Si:30]([CH3:47])([CH3:46])[O:31][CH:32]1[CH:37]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35][N:34]([CH2:24][CH2:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:15]2)[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Product: CC(C)(C)[Si](C)(C)OC1CCN(CCCCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CC1O[Si](C)(C)C(C)(C)C

Procedure:
In analogy to the procedure described in example 163A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) and (trans)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 26) gave the title compound as colorless oil.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:17]=[N:18][C:19]=2[CH3:20])=[N:9][CH:8]=1>O.C1COCC1.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=3)=[C:19]([CH3:20])[N:18]=[N:17]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A solution of lithium hydroxide monohydrate (143 mg, 3.39 mmol) in water (5.8 mL) was added dropwise to a suspension of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid methyl ester (581 mg, 1.7 mmol) in THF (5.8 mL) and methanol (2 mL). The reaction mixture was then stirred at room temperature for 30 min and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (538 mg, 97%) as a white solid. MS: m/e=327.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][CH2:41][CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].O>C(Cl)Cl>[CH3:53][S:54]([O:43][CH2:42][CH2:41][CH2:40][C@H:10]1[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:56])=[O:55]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)propanol (3.35 g, 5.75 mmol) in CH2Cl2 (30 mL) at 0° C. was added DIPEA (1.25 mL, 7.19 mmol) and followed by dropwise addition of methanesulfonyl chloride (538μL, 6.9 mmol). After stirring at 0° C. for 1 hr, the reaction mixture was poured into water (50 mL). The organic layer was separated and washed with sat'd NaHCO3 (50 mL), brine (30 mL), dried over MgSO4, filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.76-1.90 (m, 3H), 1.90-1.99 (m, 2H), 3.00 (s, 3H), 3.58-3.66 (m, 2H), 3.68-3.74 (m, 2H), 3.77-3.85 (m, 2H), 4.06 (m, 1H), 4.52 (d, J=10.7, 1H), 4.54 (d, J=12.1, 1H), 4.65 (d, J=12.1, 1H), 4.66 (d, J=11.6, 1H), 4.76 (d, J=11.6, 1H), 4.85 (d, J=10.9, 1H), 4.98 (d, J=10.9, 1H), 7.18 (m, 2H), 7.30-7.40 (m, 18H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:16])[CH2:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:31](=[O:32])[C:28]3[CH:29]=[CH:30][C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:26][CH:27]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:16])[CH2:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C)c(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1c2cc(C)c(NC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 l) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](I)[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]2[CH2:9][CH2:8][CH:7]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH2:6]2)[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Ic1cccc(OCc2ccccc2)c1
Reactant: C=CCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2cccc(OCc3ccccc3)c2)C1

Procedure:
The title compound, MS: m/e 464.3 (M−H+) was prepared from (RS)-4-(1-but-3-enyl-pyrrolidine-3-sulfonyl)-phenol and benzyl-(3-iodo-phenyl)-ether. Benzyl-(3-iodo-phenyl)-ether is a known compound and has been prepared as described in the following reference: W. Kipping; J. Chem. Soc.; 1957; 3246-3250.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]2[C:19]3[CH:18]=[C:17]4[O:20][CH2:21][CH2:22][O:23][C:16]4=[CH:15][C:14]=3[N:13]([CH2:24][C:25]3[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12]2=[O:34])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:31][C:30]([F:33])([F:32])[C:27]1[O:26][C:25]([CH2:24][N:13]2[C:14]3[CH:15]=[C:16]4[O:23][CH2:22][CH2:21][O:20][C:17]4=[CH:18][C:19]=3[C:11]3([C:10]4=[CH:9][C:5]5[CH2:6][CH2:7][O:8][C:4]=5[CH:3]=[C:2]4[O:1][CH2:35]3)[C:12]2=[O:34])=[CH:29][CH:28]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one was obtained (42%) as a colorless solid: mp 189-191° C.; 1H NMR (300 MHz, CDCl3) δ6.77-6.73 (m, 1H), 6.72 (s, 1H), 6.52-6.45 (m, 2H), 6.43-6.36 (m, 2H), 4.91 (ABq, 2H), 4.77 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.27-4.14 (m, 4H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 161.8, 161.0, 151.9, 143.9, 140.1, 135.2, 124.9, 120.2, 120.0, 118.8, 113.6, 112.6 (d, J=2.8 Hz, 1C), 109.2, 98.8, 93.1, 80.4, 72.4, 64.6, 64.0, 57.5, 37.0, 28.9; MS (ES+) m/z 485.9 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9]>O>[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[Ca+2:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Solid preparations of calcium carbonate and citric acid in exactly desired ratio are mixed. When this mixture is added to water, the reaction of the two compounds yields calcium citrate, with elaboration of carbon dioxide. An excess of citrate renders calcium citrate increasingly soluble.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C=O)C>[C:13]1(=[O:23])[N:17]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[O:11][CH3:12])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(C#N)ccc1CBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
24.4 g (108 mol [sic]) of 4-bromomethyl-3-methoxybenzonitrile, dissolved in 125 ml of DMF, and 20.0 g of potassium phthalimide were stirred at room temperature for 24 h and then at 50° C. for 1 h. The mixture was poured into water, whereupon the product precipitated as solid. 21.5 g (68%) were obtained. 1H-NMR (DMSO-d6 ; δ in ppm): 7.9 (m, 4H); 7.5 (d, 1H); 7.35-7.25 (m, 2H); 7.78 (s, 2H); 3.92 (s, 3H)
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[C:4](=[O:19])[N:3]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][CH:2]1[CH2:6][C:5]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:4](=[O:19])[N:3]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1
Reactant: CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl 3-methyl-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (90 mg, 0.257 mmol) was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated to remove excess of the reagent and co-evaporated with dichloromethane three times to give the title compound. LC-MS (IE, m/z): 251 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([S:14][CH3:15])=[CH:12][C:11]([N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:23](=[O:26])([O-])[O-:24].[K+].[K+]>CN(C=O)C.CO.O>[C:3]([O:24][C:23](=[O:26])[NH:22][CH:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[C:13]([S:14][CH3:15])[C:3]3[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=3[CH:10]=2)[CH2:21][CH2:20]1)([CH3:13])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CSc1cc(N2CCC(N)CC2)cc2sc(C(N)=O)c(N)c12
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Yield: 206.4 %

Procedure:
To a solution of 0.211 g (0.577 mmol) of the above amide in DMF (5 mL) was added 1.6 mL (1.8 mmol) of a 10% solution of 2-thioacetamide in MeOH along with 0.80 g (5.8 mmol) of potassium carbonate. The mixture was heated to 70° C. for 15 h then cooled to room temperature and diluted with H2O which caused a solid to precipitate from solution. The solid was collected by filtration, washed with H2O and dried under vacuum to provide 0.260 g (100%) of [1-(3-amino-2-carbamoyl-4-methylthio-benzo[b]thiophen-6-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:43][CH2:42][C:17]([CH3:44])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([F:41])[C:26]([F:40])=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:43][CH2:42][C:17]([CH3:44])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([F:41])[C:26]([F:40])=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:16][CH2:15]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(F)c(F)cc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCc1cc(F)c(F)cc1COC3
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{15,16-difluoro-4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (60 mg, 0.098 mmol) and NaOH (3.90 mg, 0.098 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt and purified by preparative HPLC to isolate (2S)-2-(tert-butoxy)-2-{15,16-difluoro-4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetic acid (32.5 mg, 55.6%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.44-7.31 (m, 1H), 7.27 (dd, J=11.6, 8.6 Hz, 1H), 6.51 (s, 1H), 5.71 (s, 1H), 4.97-4.76 (m, 3H), 4.62 (d, J=12.5 Hz, 1H), 4.49 (t, J=11.2 Hz, 1H), 3.63-3.53 (m, 2H), 3.21-3.19 (m, 2H), 2.68-2.56 (m, 3H), 2.50 (br. s., 3H), 1.83 (d, J=12.8 Hz, 3H), 1.71-1.50 (m, 5H), 1.18 (s, 3H), 1.15 (s, 9H). LCMS (M+1)=587.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:45])=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:45])=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K8) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous brown substance (201 mg).