Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c5c(cnc4n3S(=O)(=O)c3ccc(C)cc3)cnn5C)c2c1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
7-(5-Methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.100 g, 0.212 mmol; Preparation #P.1.1) and 60 wt % NaH (0.009 g, 0.212 mmol) were suspended in DMF (3 mL). After about 10 min, 2-chloro-N,N-dimethylacetamide (0.052 g, 0.424 mmol, Pfaltz-Bauer) was added and mixture was stirred at rt. After about 1 h additional 60 wt % NaH (0.005 g, 0.212 mmol) was added and the mixture was heated to about 40° C. for about 16 h. The mixture was concentrated in vacuo and purified on a 4 g silica column eluting with EtOAc to provide 2-(5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-1-yl)-N,N-dimethylacetamide (0.097 g, 82%): LC/MS (Table 2, Method c) Rt=1.46 min; MS m/z 557 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](F)=[O:5].[Cl-:12].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: O=C(F)c1ccc(F)cc1F
Reactant: [Cl-]
Agent: [Al+3]
Product: O=C(Cl)c1ccc(F)cc1F
Temperature: 90 °C

Procedure:
13.5 g (.085 mol) of 2,4-diflurobenzoylfluoride were cooled to about 5° C. Aluminum chloride (3.7 g; 0.028 mol) was added slowly over about 0.5 hour. The conversion to the aroyl chloride was 80% (as determined by Gas Chromatography). The reaction was warmed to 90° C. Complete conversion of the starting material resulted. The product was distilled at reduced pressure to yield 2,4-difluorobenzoylchloride as a colorless liquid. This material was not assayed but used directly in the reduction step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[CH:28]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K82) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (53 mg).
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:23]([NH:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH:11][C@H:2]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3]2)[CH:21]=[CH:20]3)=[NH:26])[CH2:29][CH2:28]1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NC1CC1
Agent: I
Product: N=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CC1

Procedure:
The title compound was prepared in accordance with the general method 16 described in example 151 from 1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide and cyclopropylamine; MS: m/e=358.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].I[CH3:16]>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([O:14][CH3:16])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Reactant: CI
Product: COc1cnc2c([N+](=O)[O-])cccc2c1
Yield: 26 %

Procedure:
In a manner analogous to that described in Example 30 a) the alkylation of the 8-nitro-quinolin-3-ol (CAS25369-37-3) with iodomethane yielded the title compound as a yellow solid (yield 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([OH:28])[CH3:27])[NH:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35]>CN(C)C1C=CN=CC=1.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([O:28][C:33](=[O:34])[CH2:32][CH2:31][C:30]([OH:35])=[O:29])[CH3:27])[NH:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)O1
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(OC(=O)CCC(=O)O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
N—((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxy-ethyl)-1H-pyrazole-3-carboxamide (1.254 mmol, 0.5 g), dihydrofuran-2,5-dione (1.504 mmol, 0.151 g) and 4-dimethylaminopyridine (0.1254 mmol, 0.015 g) were dissolved in THF (10 ml) and DMF (1 ml). The resulting mixture was stirred at RT for one day after which the temperature was raised to 50° C. for one day. The mixture was stirred at RT over the weekend. During the reaction more dihydrofuran-2,5-dione (50 mg) was added. The solvents were evaporated and the residue was dissolved in EtOAc. The organic phase was washed with 1 M HCl, separated, dried, filtered and evaporated. The crude product was purified by flash chromatography. 352 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.22-1.28 (m, 3H), 1.61-1.69 (m, 3H), 2.54-2.79 (m, 4H), 4.29-4.45 (m, 2H), 4.52-4.64 (m, 1H), 5.97-6.06 (m, 1H), 6.58-6.62 (m, 1H), 6.76-6.80 (m, 1H), 7.50-7.53 (m, 1H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 1H), 7.90-8.04 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[C:9]1([N:6]2[CH:7]=[CH:8][C:4]([NH2:1])=[CH:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1ccn(-c2ccccc2)c1
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 3-nitro-1-phenyl-1H-pyrrole (410 mg, 2.18 mmol) and SnCl2 dihydrate (2.00 g, 8.86 mmol) in EtOAc (15 mL) was stirred at 80 C for 3 h. Aqueous 1N NaOH was added to bring pH to 12. The mixture was filtered through celite. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-phenyl-1H-pyrrol-3-amine as a solid (323 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazole-2-one was treated with ethyl 3-bromo-propionate and potassium carbonate in butanone to give after work-up the title compound. m.p. 111°-112° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[CH2:49])[CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][N:26]=3)[CH:13]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[CH:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][C:3]([CH2:2][Cl:1])=[CH2:49])=[CH:7][CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=2)=[N:26][CH:27]=1
Reactant: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cn3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CN)cn3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of tert-butyl (3-(6-((6-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (45 mg) in DCM (3 mL) was added TFA (0.3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give N-(3-amino-2,2-dimethylpropyl)-6-(6-(4-(2-(chloromethyl)allyloxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamide (30 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C@@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)=[O:5])[CH3:2].[ClH:35]>ClCCl>[ClH:35].[CH2:1]([NH:3][CH:4]([OH:5])[CH2:6][C@@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[C:9](=[C:10]([O:19][CH:20]4[CH2:21][CH2:22][CH:23]([NH:26][CH3:27])[CH2:24][CH2:25]4)[N:11]=[CH:12][N:13]=3)[C:8]1=2)[CH3:2]
Reactant: CCNC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CCNC(O)C[C@@H]1CCc2sc3ncnc(OC4CCC(NC)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25-mL round-bottom flask was added 24.1 (165 mg, 0.34 mmol, 1.00 equiv) and hydrochloric acid (12 M, 2 mL) in dichloromethane (12 mL). The reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford 1-(ethylamino)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-ol hydrochloride (105 mg, crude) as a yellow oil that was used in the next step without further purification. To a solution of this compound (105 mg, crude) in methanol (10 mL) was added HCHO (37%, 2 mL) and the reaction was stirred for 1 h at room temperature. Then NaBH3CN (50 mg, 63%) was added and the reaction stirred for another 2 h at ambient temperature. The resulting mixture was concentrated under reduced pressure and the crude product (85 mg) purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water (0.05% NH4HCO3) and CH3OH NMR (6.0% CH3OH up to 50.0% in 25 min); UV detection at 254 nm. The fractions were collected and evaporated under reduced pressure to give the desired Compound I-36 (43 mg) as a white solid. An enantiomeric excess of 100% was measured by chiral HPLC analysis. 1H NMR (400 MHz, CD3OD): δ 8.48 (s, 1H), 5.30 (m, 1H), 3.84 (m, 1H), 2.94-3.32 (m, 5H), 2.73 (m, 1H), 2.20-2.68 (m, 11H), 1.50-1.72 (m, 4H), 1.15 (t, 3H). MS: m/z 403 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])[CH2:14][CH3:15]>C(O)C>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH2:13][CH2:14][CH3:15])[CH:18]=1
Reactant: CCCOc1cc(CN)ccc1OC
Reactant: O=c1[nH]nc([N+](=O)[O-])c(Cl)c1Cl
Solvent: CCO
Product: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 15 h

Procedure:
A mixture comprising 8.0 g of 4,5-dichloro-6-nitro-3(2H)pyridazinone, 29.75 g of 3-n-propoxy-4-methoxybenzylamine and 160 ml of ethanol, was refluxed under stirring for 15 hours. Ethanol was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain an orange solid substance. This product was crystallized from a solvent mixture of methanol-water, to obtain 6.50 g of the above identified compound having a melting point of from 169° to 171° C. as orange crystals.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:18]=1>>[C:1]1([CH:7]([CH3:11])[C:8]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]4[C:32]5[C:37]([CH:38]=[CH:39][C:24]3=4)=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:19][CH:18]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)c1ccccc1
Yield: 22.2 %

Procedure:
2-Phenylpropionic acid (30 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (10 mg, yield 22%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13](S(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:24][CH:23]=2)[C:3]1=[O:40].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:41])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=2)=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:26][CH:27]=2)[C:3]1=[O:40]
Reactant: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(c2ccc(NS(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a stirred solution of N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (40 mg, 0.06 mmol) in THF: H2O (6 mL) was added 2N NaOH (1.0 mL) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. Upon complete consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)methane sulfonamide (20 mg, 26%), as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.45 (d, J=8.5 Hz, 1 H), 8.12 (t, J=7.9 Hz, 1H), 7.78 (t, J=8.4 Hz, 1 H), 7.70 (d, J=8.2 Hz, 1 H), 7.64 (t, J=8.2 Hz, 1 H), 7.44 (d, J=8.5 Hz, 2 H), 7.18 (d, J=7.5 Hz, 2 H), 7.10 (d, J=7.5 Hz, 2 H), 6.98 (d, J=8.2 Hz, 2H), 5.42 (s, 2 H), 2.85 (s, 3 H), 1.44 (s, 6H). MS: [M+Na]: m/z=537.3, [M+H]: m/z=515.2 HPLC: 95.7% (RT-2.37 min), Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)=O.CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:25][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: CCCCCc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
A solution of 15.3 g of tetrabromomethane in 150 ml of methylene chloride was placed at 0° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 12.1 g of triphenylphosphine in 50 ml of methylene chloride. After completion of the addition, the clear orange reaction solution was stirred at 0° C. for a further 5 minutes and then a solution of 5.80 g of 4-formyl-4'-pentylbiphenyl in 50 ml of methylene chloride was added dropwise within 10 minutes. After stirring at 0° C. for a further 45 minutes, the yellow-orange mixture was poured into 1000 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 400 ml of hexane, left to stand at 0° C. for 18 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (9.8 g) on silica gel with hexane gave 5.15 g (55%) of 4-(2,2-dibromovinyl)-4'-pentylbiphenyl as colourless crystals (purity 99.1%); m.p. 95° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:19][C:18]3[C:20]([CH3:27])=[C:21]([OH:26])[C:22]([CH3:25])=[C:23]([CH3:24])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:19][C:18]3[C:20]([CH3:27])=[C:21]([O:26][CH2:34][C:33]4[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)[C:22]([CH3:25])=[C:23]([CH3:24])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)CC2(CCN(Cc4ccccc4)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 134.6 mg, 3.37 mmol) was added to a solution of 1′-benzyl-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (1.01 g. 2.98 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (584.9 mg, 3.43 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (1.15 g, yield 85%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:25]([Si:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][CH2:10][CH2:9][NH:7][CH3:6])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 24.3 %

Procedure:
[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (572 mg, 1.38 mmol) and 4M HCl/dioxane (3 mL) in CH2Cl2 (5 mL) were stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and the crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 10% MeOH/CH2Cl2 to obtain [2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-methyl-amine as a yellow solid (105 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CSc1ccc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 45.2 %

Procedure:
Into a solution of methyl 5-(3,4-dichlorophenylthio)-4-(N,N-dipentylcarbamoyl)pentanoate (5.12 g) in dry dichloromethane (100 ml) were added portions of m-chloroperbenzoic acid (70%, 2.65 g) with stirring at -78° C. After stirring at -78° C. for 2 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with dichloromethane/diethyl ether/hexane (1:1:2) to give 2.39 g of methyl 5-(3,4-dichlorophenylsulfinyl)-4-(N,N-dipentylcarbamoyl)pentanoate (diastereomer A) in a early fraction and 2.47 g of diastereomer B in a later fraction.
Reaction SMILES: ClC1C=CC(C(C2C=CC(I)=CC=2)(O)CNCCO)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:42]=[N:43][NH:44][CH:45]=4)=[CH:37][CH:36]=3)[O:34]C[CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1.CN>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:45]=[N:44][NH:43][CH:42]=3)=[CH:37][CH:36]=2)([OH:34])[CH2:30][NH:31][CH3:32])=[CH:25][CH:24]=1
Reactant: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1
Agent: CN
Agent: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Product: CNCC(O)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 79A, 79B and 79D but substituting ethanolamine for methylamine, the title compound was obtained. LCMS (PS-A3) Rt 5.28 min [M+H]+ 328, [M−H2O+H]+ 310. 1H NMR (Me-d3-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).