Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[N:13](C(=O)C)[CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl>C(#N)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Agent: Cl
Solvent: CC#N
Product: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-yl)ethanone (1.35 g, 4.27 mmol) in acetonitrile (30 mL) was treated with 2.0M aqueous HCl (12 mL). The reaction was stirred at rt overnight and then it was heated to 120° C. for 36 h. After this time the reaction was cooled to rt and quenched with aqueous NaOH. The mixture was partitioned between EtOAc (200 mL) and water (80 mL). The separated organic layer was washed with NaHCO3 (saturated aqueous solution) and then it was dried over MgSO4, filtered and evaporated in vacuo to give 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] as a pale solid. Mass Spectrum (ESI) m/e=275 (M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])C.C(O)C>[OH-].[Na+]>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCc1cccc2cncn12
Reaction time: 0.75 h

Procedure:
A suspension of 26 g of 5-(5-ethoxycarbonylpentyl)imidazo[1,5-a]pyridine in 100 ml of 1 N aqueous sodium hydroxide solution is heated on a steam bath for two hours; 10 ml of ethanol is added and heating is continued for 45 minutes. The reaction mixture is cooled, washed with 300 ml of ether and the solution is adjusted to pH 5.5 with concentrated hydrochloric acid. The crystallized product is collected by filtration and washed with 50 ml of water to yield 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 144°-7°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: Cc1cccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)c1

Procedure:
The product of Example 86A and 2-(3-methylphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.74 (m, 1H), 7.60-7.66 (m, 4H), 7.24 (t, J=7.5 Hz, 1H), 7.19-7.21 (m, 1H), 7.16-7.19 (m, 1H), 7.08-7.12 (m, 1H), 3.65 (s, 2H), 2.31 (s, 3H); MS (ESI−) M/Z 402 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH2:10].[Cl-].[Cl-].[Cl-].[Al+3].[Al].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[CH3:10][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH2:8][Si:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CC[Si](C)(C)C
Reactant: Nc1ccccc1
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C[Si](C)(C)C)c1ccccc1N
Temperature: 255 °C
Reaction time: 10 h
Yield: 3.6 %

Procedure:
17.7 g of aniline (0.19 mol), 50 g of allyltrimethylsilane (0.44 mol), 1.5 g of aluminum trichloride (0.01 mol) and 0.5 g of aluminum powder (0.02 mol) were mixed and stirred in an autoclave at 255° C. for 10 h. After cooling to room temperature, initially 100 ml of toluene and then 40 ml of a 40% strength solution of NaOH in water and 100 ml of water were added, and the mixture was stirred at 35° C. for 15 min. After cooling, the mixture was extracted with toluene, the extract was washed with water and dried over potassium carbonate and the solvent was removed under reduced pressure. Distillation (55° C.-60° C., 0.08 mbar) gave 1.4 g of 2-(1-methyl-2-trimethylsilylethyl)phenylamine [log P (pH 2.3)=3.05].
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:40])[NH:30][C:31]3[C:36]\2=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:47]>>[ClH:47].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:40])[NH:30][C:31]3[C:36]\2=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4I)(=[O:21])=[O:20])[CH2:15][CH2:14]3)[C:10]2=[O:29])=[CH:5][CH:4]=1)[CH3:2].[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35].C([O-])([O-])=O.[K+].[K+].CNCCNC>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[C:10]2=[O:29])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4I)CC3)C2=O)cc1
Reactant: O=C1CCCN1
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4N4CCCC4=O)CC3)C2=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-ethyl-phenyl)-8-(2-iodo-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.06 g), compound of example 74), 2-pyrrolidinone (0.015 g), K2CO3 (0.055 g) and N,N′-dimethylethylenediamine (0.015 g) was heated in DMF under an argon atmosphere for 24 h at 150° C. The mixture was then cooled to RT and extracted with AcOEt. The extracts were combined, filtered, washed with water and dried over sodium sulphate. The solvent was removed in vacuo. The residue was chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 50%, then MeOH/CH2Cl2 from 0 to 7%) to give the desired 2-(4-ethyl-phenyl)-8-[2-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-2,8-diaza-spiro[4.5]decan-1-one as a yellow oil. MS (ESI): 482.21 (MH+).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Na].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1>C(O)C>[ClH:1].[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CNC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Brc1ccc(N2CCC2)nc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Azetidine hydrochloride (3.0 g, 32.1 mmol) was added to a solution of sodium (0.73 g, 31.7 mmol) in ethanol (25 ml) and the solution stirred vigorously for an hour. 2,5-Dibromopyridine (5.0 g, 21.1 mmol) was then added and the reaction mixture heated at 100° C. for 10 hours in a sealed vessel, and then at 120° C. for a further 10 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The layers were separated, the aqueous phase was extracted with ethyl acetate (3×), and the combined organic extracts washed with brine, dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by medium pressure column chromatography on silica gel, using dichloromethane:pentane (66:34) as eluant to give the tile compound, (900 mg, 17%) as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[Br:21]N1C(=O)CCC1=O.CSC>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:21])=[CH:4][C:3]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(I)c(Oc2ccc3ccccc3c2)c1
Solvent: ClCCl
Solvent: CSC
Product: BrCc1ccc(I)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
To a solution of [4-iodo-3-(naphthalen-2-yloxy)-phenyl]-methanol (0.085 g, 0.226 mmol) in CH2Cl2 (2 mL) at −15° C. was added a cold (0° C.) solution of N-bromosuccinimide (0.120 g, 0.68 mmol) in dimethyl sulfide (0.060 mL, 0.814 mmol) with stirring. The reaction mixture was allowed to warm to ambient temperature overnight, concentrated to dryness, and chromatographed (SiO2, 10% EtOAc:hexane) to give the title compound which was used without purification.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]([OH:32])=[O:31]>[Pd]>[C:30]([OH:32])(=[O:31])[CH3:29].[N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CCN(C(=O)OCc1ccccc1)C2CN1CCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc2c1CCNC2CN1CCCC1

Procedure:
0.840 g (2.21 mmoles) of (+)-1-(pyrrolidin-1-yl)methyl-2-benzyloxycarbonyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline were hydrogenated in 90% CH3COOH at 30 psi, 3 hours, at room temperature over 100 mg of 5% Palladium on activated charcoal.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4]1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([O:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4]1)[CH3:15])[CH3:12]
Reactant: C=COCC
Reactant: CC1(C)C[C@H](CO)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(C)OC[C@H]1CC(C)(C)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
To a solution of (R)-5-hydroxymethyl-3,3-dimethyl-pyrrolidin-2-one (4.0 g, 28 mmol), prepared as described in Tetrahedron 1998, 54 10295-10307, and ethyl vinyl ether (4 mL, 42 mmol) in chloroform (26 mL), was added a catalytic amount of trifluoroacetic acid (0.056 mL), and the reaction mixture was stirred for four hours at room temperature. The solution was then washed with a saturated solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude oil obtained after evaporating the solvent, was purified by chromatography on silica gel using hexane:ethyl acetate 1:1 as a solvent, giving 2.6 g of (R)-5-(1-ethoxy-ethoxymethyl)-3,3-dimethyl-pyrrolidin-2-one.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])(=O)C1C=CC=CC=1.[OH-].[Na+]>O.C(O)C>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([OH:9])[CH:15]=1
Reactant: COc1ccc(Br)cc1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)cc1O
Yield: 98.3 %

Procedure:
A solution of 2-benzoyloxy-4-bromoanisole (5 g) and sodium hydroxide (3 g) in water (5 mL) and ethanol (50 mL) is heated at reflux for 1 hour 30 minutes. It is then evaporated and the residue is triturated with water (20 mL) and concentrated hydrochloric acid (10 mL) and extracted with dichloromethane (150 mL). The organic solution is washed with saturated aqueous sodium bicarbonate solution (3×25 mL), dried, and concentrated, to give 5-bromo-2-methoxyphenol (3.25 g), in the form of a white crystalline solid, m.p. 67-68° C.
Reaction SMILES: C(NC(C1SC(N2C(O)CN(CC3C=CC(F)=CC=3)C2=O)=NC=1C)=O)C1C=CC=CC=1.O[CH:33]1[N:37]([C:38]2[S:39][C:40]([C:44]([NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:45])=[C:41]([CH3:43])[N:42]=2)[C:36](=[O:54])[N:35]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)[CH2:34]1>>[CH3:43][C:41]1[N:42]=[C:38]([N:37]2[CH:33]=[CH:34][N:35]([CH2:55][C:56]3[CH:57]=[CH:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=3)[C:36]2=[O:54])[S:39][C:40]=1[C:44]([NH:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:45]
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(C(F)(F)F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Agent: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 81 %

Procedure:
Following the procedure as described in Example 17, making variations as required to replace N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide with 2-(5-hydroxy-2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 81% yield: mp 163-164° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.58-8.48 (m, 2H), 7.71-7.67 (m, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.29-7.21 (m, 3H), 6.29 (d, J=3.3 Hz, 1H), 4.82 (s, 2H), 4.53 (d, J=5.7 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 153.5, 153.4, 150.5, 149.2, 148.9, 139.5, 135.8, 133.7, 130.8, 128.4, 128.1, 126.0, 122.0, 119.6, 113.1, 107.9, 46.9, 41.5, 17.3; MS (ES+) m/z 474.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:15]1
Reactant: CS(=O)(=O)OC1CCN(CC2CC2)C1
Reactant: Oc1ccccc1Br
Product: Brc1ccccc1OC1CCN(CC2CC2)C1

Procedure:
The title compound was prepared from 2-bromophenol and 1-(cyclopropylmethyl)pyrrolidin-3-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][O:16]C3CCCCO3)[C:6]=2[CH:23]=1.CC(O)=O.C1COCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][OH:16])[C:6]=2[CH:23]=1
Reactant: O=c1cc(OCCCOC2CCCCO2)c2cc(Br)ccc2o1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1cc(OCCCO)c2cc(Br)ccc2o1
Yield: 39.6 %

Procedure:
6-Bromo-4-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-1-benzopyran-2-one (0.893 mmol, 0.342 g) is treated with 5 mL of 4:2:1 HOAc:THF:H2O and is heated to 45° C. for 1 hr. The solvent is removed under reduced pressure and the residue is purified by HPLC to afford the title compound (105.8 mg, 60%); 1H NMR (DMSO-d6, 300 MHz) δ 7.90 (1H, d, J=2.5 Hz), 7.82 (1H, dd, J=2.25, 8.75 Hz), 7.39 (1H, d, J=8.75 Hz), 5.96 (1H, s), 4.29 (2H, t, J=6.25 Hz), 3.61 (2H, t, J=6 Hz), 1.97 (2H, m); MS (ESI, Pos.) calcd for C12H11BrO4 m/z [M+H]=299.0, found 299.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>C1COCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:28]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[CH3:17])[NH:22][C:21]2=[O:27])=[CH:12][CH:13]=1)[CH3:16]
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cccc(C)c32)cc1
Temperature: 72 °C
Yield: 52 %

Procedure:
To a solution of 4-(3-diethylamino-propoxy)-phenylamine (913 mg, 1.3 equiv.) in THF (14 mL) is added 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (554 mg, 3.17 mmol) in one portion. The resulting reaction mixture is stirred and heated at 72° C. overnight. The reaction solution is cooled to room temperature and partitioned between EtOAc:H2O. The organic layer is collected and washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. The organic phase is filtered and concentrated. The residue obtained is triturated with 1:4 EtOAc:hexane to give the named compound as a yellow solid (625.8 mg, 52%).
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[N:9][N:10]=1)([CH3:5])[CH2:3][OH:4].C([O:32][P:33](Cl)([O:35]CC)=[O:34])C.C(N(CC)CC)C.Br[Si](C)(C)C>C(Cl)Cl>[P:33]([OH:35])([OH:34])([O:4][CH2:3][C@:2]([NH2:1])([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:28])([F:27])[F:29])[CH:12]=2)=[N:9][N:10]=1)[CH3:5])=[O:32]
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)COP(=O)(O)O)s2)cc1C(F)(F)F
Reaction time: 36 h
Yield: 5.7 %

Procedure:
Crude product from E3 (30 mg, 0.069 mmol) was added to diethylchlorophosphate (100 μL, 0.69 mmol) and triethylamine (194 μL, 1.39 mmol,) in DCM and stirred for approx 36 hrs. The reaction mixture was then condensed and treated with bromotrimethylsilan (0.3 mL) in DCM (5 mL) to provide the title compound (˜2 mg). MS (ESI): 511.98 (MH+),
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:18][CH:19](Cl)[C:20](=O)[CH3:21]>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([S:2]([F:14])([F:15])([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[O:12][CH:21]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.10 g (15.0 mmol) 3-(4-Pentafluorosulfanyl-phenyl)-acrylamide, 2.37 g (18.7 mmol) dichloro acetone and 25.0 ml toluene were kept at reflux temperature for 12 h with continuous removal of water by use of a Dean-Stark trap. The reaction mixture was evaporated and purified by chromatography on silica gel (eluent: heptane/ethyl acetate 5:1). All fractions containing the product were evaporated and the residue stirred with 10 ml isohexane, the crystallized material isolated by filtration dried. Yield: 4.40 g (85%) 4-Chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C(OCC)(=O)C.CCN(CC)CC>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])=[CH:8][CH:9]=1
Reactant: CC(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
p-Nitroisobutyrophenone from step 4 (1.0 g, 0.0058 mol), was dissolved in DMF (5 ml). SnCl2.2H2O (4.67 g, 0.0207 mol) is added and the reaction is stirred at room temperature. After 4 hours the reaction was poured into 100 ml of ethyl acetate. Excess Et3N (4 ml) was added and a white, solid precipitate formed. The suspension was filtered through celite. Evaporation of the filtrate left a yellow solid which was purified by column chromatography. The resulting crystalline solid (0.700 g, 4.2 mmol, 82%) had a 1H-NMR (DMSO): 7.71 (d, 2H), 6.58 (d, 2H), 6.03 (s, 2H), 3.45 (m, 1H), 1.06 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]([NH2:14])[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.[N:17]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=2[N+:33]([O-:35])=[O:34])[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23]>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C:18]4=[O:23])=[C:25]([N+:33]([O-:35])=[O:34])[CH:26]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
237 mg (0.93 mmol) of (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanylpropylamine are dissolved with 0.257 ml TEA in 10 ml THF and a solution of 290 mg (1.02 mmol) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid chloride in 10 ml THF is added dropwise. The reaction mixture is stirred for 16 hours at ambient temperature and then evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->95:5).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[NH2:7][C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Yield: 98.5 %

Procedure:
A solution of [3-(benzenesulfonyl-benzyl-amino)-phenyl]-carbamic acid tert-butyl ester (1.09 g, 2.49 mmol) and trifluoroacetic acid (2.5 ml) in dichloromethane (22.5 ml) were stirred at room temperature for 90 minutes. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organics were dried (magnesium sulphate) and concentrated in vacuo to afford the title compound as a brown oil (0.83 g, 99%). HPLC retention time 5.9 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:30]([O:34][C:35]([N:37]1[C:41]2=[N:42][CH:43]=[C:44]([Cl:46])[CH:45]=[C:40]2[C:39]([CH2:47]Cl)=[CH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].N>O1CCCC1>[C:30]([O:34][C:35]([N:37]1[C:41]2=[N:42][CH:43]=[C:44]([Cl:46])[CH:45]=[C:40]2[C:39]([CH2:47][C:19]2[C:18]([F:23])=[N:17][C:16]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=3)=[CH:21][CH:20]=2)=[CH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Br)c(F)n1
Agent: CC(C)[Mg]Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Cc2cn(C(=O)OC(C)(C)C)c3ncc(Cl)cc23)c(F)n1
Temperature: -35 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (143, 0.600 g, 1.50 mmol) in 10.0 mL of tetrahydrofuran at −25° C. under nitrogen, isopropylmagnesium chloride (0.730 mL, 2.0 M in tetrahydrofuran, 1.46 mmol) was added and the reaction allowed to come to 5° C. over 1 hour. The reaction was then cooled to −35° C., and CuCN-2LiCl (2.0 mL, 0.75 M in tetrahydrofuran, 1.5 mmol) was added. After 5 minutes, 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (142, 0.300 g, 0.996 mmol) in 4.0 mL of tetrahydrofuran was added and the reaction allowed to come to room temperature over 1 hour. The reaction was poured into dilute ammonia solution and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (144, 130 mg). MS (ESI) [M+H]+=586.2.