Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][CH3:13])[CH2:9][C:10]#N)(C)(C)C.CCCCCC.CC(C[AlH]CC(C)C)C.Cl.CC[O:33]CC>>[CH2:12]([C@@H:8]([NH:7][C:6](=[O:14])[OH:5])[CH2:9][CH:10]=[O:33])[CH3:13]
Reactant: CC[C@H](CC#N)NC(=O)OC(C)(C)C
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCCCCC
Product: CC[C@H](CC=O)NC(=O)O
Temperature: -40 °C
Reaction time: 3.5 h

Procedure:
To a solution of ((R)-2-cyano-1-ethyl-ethyl)-carbamic acid tert-butyl ester (10 mmol; 1.98 g) in Et2O (50 mL) is slowly added a 0.97 M n-hexane solution (40 mmol; 41 mL) of DIBAL under nitrogen at −78° C. The reaction mixture is warmed to −40° C. and stirred for an additional 3.5 hours. Another 1.00 M n-hexane solution (30 mmol; 30 mL) of DIBAL is added to the suspension at the same temperature. After stirring for additional 1.5 hours, the solution is quenched by careful addition of 1 ml of MeOH then immediately poured into 25 ml of saturated aqueous ammonium chloride solution in a separatory funnel. Shake mixture and leave until it reaches room temperature. Aqueous 1M HCl is added to reach a pH of 3-4. The solution is extracted three times with EtOAc and the combined organic layer is washed with an aqueous 1M HCl/brine (1:1) solution and twice with a saturated aqueous NaHCO3/brine (1:1) solution, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give ((R)-1-ethyl-3-oxo-propyl)-carbamic acid tent-butyl ester (590 mg, 29%); ESI-MS m/z: 146 [M+−tBu+2], Retention time 2.17 min (condition A).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([O:9][Si](C)(C)C)[C:7]#N)=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].BrC[CH2:24][CH2:25][C:26]#[N:27]>O1CCCC1>[C:26]([CH2:25][CH2:24][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:9])#[N:27]
Reactant: N#CCCCBr
Reactant: C[Si](C)(C)OC(C#N)c1ccsc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCCCC(=O)c1ccsc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2-(3-thienyl)-2-trimethylsilyloxyacetonitrile thus obtained (14.0 g.) in tetrahydrofuran (12 ml.) was added to a stirred solution of lithium diisopropylamide [prepared at 0° C. in tetrahydrofuran solution (200 ml.) from diisopropylamine (6.7 g.) and n-butyl-lithium (43.4 ml. of 1.55 molar solution in hexane)] in tetrahydrofuran (200 ml.) which was cooled to -78° C. under an atmosphere of nitrogen, and the mixture was stirred at that temperature for 15 minutes. 4-Bromobutyronitrile (9.8 g.) was added and the mixture was stirred at -78° C. for 1 hour and then at laboratory temperature for 1 hour. Aqueous N-hydrochloric acid (75 ml.) was added, the mixture was stirred at laboratory temperature for 90 minutes and the phases were then separated. The aqueous phase was extracted twice with ethyl acetate (100 ml. each time) and the combined organic phase and extract were stirred with aqueous N-sodium hydroxide solution (50 ml.) for 18 hours. The organic phase was separated, dried and evaporated to dryness and the residue was flash chromatographed on a silica gel column using a 19:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 4-cyano-1-(3-thienyl)butan-1-one.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][S:14]1.[C:28]([O:32][C:33]([N:35]([CH:48]([CH3:50])[CH3:49])[CH2:36][CH:37]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH:37]([C:38]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[S:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:39])[CH2:36][N:35]([CH:48]([CH3:49])[CH3:50])[C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:42][CH:43]=1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(CC(C(=O)O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
DIPEA (0.089 mL, 0.51 mmol) was added to a stirred suspension of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (40 mg, 0.13 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-fluorophenyl)propanoic acid (50 mg, 0.15 mmol) and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (58 mg, 0.15 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, diluted with EtOAc, washed with saturated aqueous bicarbonate and then 1N HCl. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give tert-butyl 2-(4-fluorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (50 mg, 72% yield) as a mixture of 2 diastereomers. LCMS (APCI+) [M-Boc+H]+ 444.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=1
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Product: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1
Yield: 49.4 %

Procedure:
The reaction of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine with 1-amino-2,2-dimethylpropane as described in Example 10 affords the title product in a yield of 49.4%, m.p.: 95°-98° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]1[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH2:15][CH2:14][N:13]1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:27][N:26]=1.CN(C=[O:43])C>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:28]2[CH:27]=[N:26][C:25]([N:13]3[CH2:14][C:15]4[C:16](=[O:43])[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[NH:23][C:24]=4[CH:12]3[CH:4]3[CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[O:3]3)=[N:30][CH:29]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cnc(N3Cc4c([nH]c5ccccc5c4=O)C3C3Cc4ccccc4O3)nc2)cc1

Procedure:
Sodium hydride (60% in mineral oil, 87 mg, 2.18 mmol) and 1-(2,3-dihydro-5-benzfuranyl)-2,3,4,9-tetrahydro-2-[5-(4-methoxyphenyl)-2-pyrimidinyl]-1H-β-carboline (450 mg, 0.95 mmol) (prepared as in Example 46) in DMF (30 mL, anhydrous) were stirred at room temperature for 30 min. Dry air was then bubbled through the solution for 16 h. Ethyl acetate (200 mL) was then added to the solution. The resulting mixture was washed with 10% NaCl solution, brine and then dried with MgSO4. The solvent was evaporated and the residue triturated with ethyl acetate to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH3:15])[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[NH:16][C:17](=[O:32])[C@H:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:16][C:17](=[O:32])[C@H:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21]
Reactant: CCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC(=O)O)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
650 mg (1.33 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)pentanoate (diastereomer mixture) were dissolved in 2 ml of acetic acid, 1 ml of 30% strength sulphuric acid was added and the mixture was heated at reflux (bath temperature about 140° C.). After 1.5 h, the reaction mixture was cooled and added to water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After drying under high vacuum, the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 600 mg of the target product (95% of theory).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1.N([O-])=[O:21].[Na+]>S(=O)(=O)(O)O.O>[OH:21][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1
Reactant: O=N[O-]
Reactant: CCCN(CCC)C(=O)C1CSc2ccc(N)cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCN(CCC)C(=O)C1CSc2ccc(O)cc21

Procedure:
11.6 g of 5-amino-2,3-dihydro-N,N-dipropyl-3-benzothiophencarboxamide were dissolved in a mixture of 4 ml of conc. sulphuric acid and 40 ml of water. 3.1 g of sodium nitrite dissolved in 10 ml of water were added dropwise below 10° C. with stirring. After addition the mixture was stirred for further 0.5 hours. The diazonium solution was then added carefully to a pre-heated solution of 50 ml of conc. sulphuric acid in 40 ml of water at 115°-120° C. The resulting mixture was poured onto ice and subsequently extracted with dichloromethane. Yield of the title compound as a semicrystalline product: 8.7 g.
Reaction SMILES: ClCl.[OH-:3].[Na+:4].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[C:16](=[O:18])C)=[CH:8][CH:7]=1.[Cl:19][O-].[Na+]>>[Cl:19][O-:3].[Na+:4].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[C:16]([OH:18])=[O:3])=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: CC(=O)c1cccc2ccc(Br)cc12
Agent: ClCl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1cccc2ccc(Br)cc12
Temperature: 0 °C

Procedure:
A sodium hypochlorite solution was prepared by introducing chlorine gas (28 g, 0.79 mole) into a solution of NaOH (38 g) in 600 ml of ice water. Solid (7-bromo-1-naphthalenyl)ethanone (19.7 g, 0.079 mole) was added to the stirred sodium hypochlorite solution at 0° C. and then the mixture was heated on a steam bath for 1 hr. The precipitate was removed by filtration. Sodium metabisulfite (10 g) was added to the cooled (0° C.) filtrate. The mixture was adjusted to pH 5 with concentrated HCl. The precipitate was collected and dried. The collected precipitate was crystallized from boiling ethanol by the addition of water to afford 14.7 g (two crops) of the title compound; mp 227-230° C.; NMR (CDCl3) δ 7.55-8.35 (m, 5H), 9.11 (d, J=2 Hz, 1H); IR (CHCl3) 2800, 1672, 1609, 1683, 1668 cm-1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][N:20](C(OCC2C=CC=CC=2)=O)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[CH3:29])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:40])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=1)[C:63]([OH:65])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][CH2:19][C@H:13]([N:10]1[CH2:11][CH2:12][C@H:8]([NH:7][C:63](=[O:65])[C:62]2[CH:66]=[CH:67][CH:68]=[C:60]([C:59]([F:58])([F:70])[F:69])[CH:61]=2)[C:9]1=[O:40])[C@@H:14]([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC#C[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 3 h

Procedure:
A solution of {(3S)-1-[(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pent-3-ynyl)]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1.16 g, 1.74 mmol) was dissolved in CH2Cl2 (16 mL) and treated with TFA (8 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. A portion (0.22 mmol) of the product amine was dissolved in CH2Cl2 (4 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (0.16 mL, 0.88 mmol), 4-dimethylaminopyridine (24 mg, 0.22 mmol), meta-trifluoromethylbenzoic acid (41 mg, 0.22 mmol), and BOP (96 mg, 0.22 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged with 5% Pd/C, Degussa style (50 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder after lyopholization. MS found: (M+H)+=506.6.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>CCCCCC>[F:14][C:15]1[C:20]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a mixture of lithium diisopropylamide (1.5M in cyclohexane, 43 mL) and tetrahydrofuran (60 mL) cooled to -70° C. was added 2-fluoropyridine (6.0 mL) at such a rate that the temperature remained below -70° C. After 1.5 hours, tributyltin chloride (15 mL) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with hexane, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (cyclohexane/ethyl acetate 98/2) gave 2-fluoro-3-tributylstannylpyridine (17 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:21][CH2:20][C:19]([C:28]([O:30]CC)=[O:29])([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:17]3)[O:12][C:11]2=[O:33])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:21][CH2:20][C:19]([C:28]([OH:30])=[O:29])([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]3)[O:12][C:11]2=[O:33])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CC1(C(=O)OCC)CCN(CC2CN(c3ccc(C(=N)N)cc3)C(=O)O2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)c1ccc(N2CC(CN3CCC(CC(=O)O)(C(=O)O)CC3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.8 g of 3-(4-amidinophenyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)-oxazolidin-2-one [obtainable accord to Ex. 9] are suspended in 60 ml of methanol, treated with 10 ml of 2N of NaOH solution and stirred at room temperature for 4 hours. After removal of the solvent, the residue is taken up in water, the pH is adjusted to 3 by addition of dilute HCl and the reaction mixture is filtered through an ion exchanger. After extraction with ethyl acetate the filtrate is dried over MgSO4. After removal of the solvent and subsequent freeze-drying, 3-(4-amidinophenyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one is obtained.
Reaction SMILES: [CH:1]([N:4]([CH:21]([CH3:23])[CH3:22])[C:5]([S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14]C(=O)C(C)(C)C)=[S:6])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:21]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])=[S:6])([CH3:23])[CH3:22]
Reactant: CC(C)N(C(=S)Sc1cnccc1NC(=O)C(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C(=S)Sc1cnccc1N)C(C)C
Temperature: 20 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
A mixture of 4-pivalamidopyridin-3-yl diisopropylcarbamodithioate (5.0 g, 14 mmol) and NaOH (1.1 g, 28 mmol) in MeOH (100 mL) was stirred at 20° C. for 20 hours. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with EtOAc/petroleum ether (1:8) to give the desired product as a white solid (3.8 g, 93% yield). 1H NMR (500 MHz, CDCl3): δ 8.24 (t, J=2.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.90 (s, 2H), 1.64-1.30 (m, 14H). LCMS (ESI) m/z: 270.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][C:16]1[C:20](B(O)O)=[C:19]([CH3:24])[O:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[Cl:14][C:4]1[CH:3]=[C:2]([C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:24])[CH:13]=[CH:12][C:5]=1[NH:6][CH2:7][C:8]([F:11])([F:10])[F:9]
Reactant: Cc1noc(C)c1B(O)O
Reactant: FC(F)(F)CNc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc(NCC(F)(F)F)c(Cl)c1
Temperature: 90 °C

Procedure:
A mixture of 4-Bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline (5280 mg, 18.3 mmol), 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (4082.76 mg, 18.3 mmol), PEPPSI″-IPr catalyst (1247.24 mg, 1.83 mmol), Cesium carbonate (17889.52 mg, 54.91 mmol) in 120 mL DME:H2O (2:1) was heated to 90° C. under argon. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with water then brine and dried over sodium sulfate. Purification on silica gel (Hexanes/EtOAc) afforded 2-chloro-4-(3,5-dimethylisoxazol-4-yl)-N-(2,2,2-trifluoroethyl)aniline.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14](I)[N:13]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:12]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC1C(OCC2C=CC=CC=2)=CN(C2C=CC(OC)=CC=2)C=1C(N(C)C)=O)C1C=CC=CC=1.C([Mg]Cl)(C)C.[CH3:77][P:78](Cl)([CH3:80])=[O:79]>C1COCC1>[CH2:3]([O:10][C:11]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([P:78]([CH3:80])([CH3:77])=[O:79])[N:13]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:12]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CP(C)(=O)Cl
Reactant: COc1ccc(-n2c(I)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: CC(C)[Mg]Cl
Agent: COc1ccc(-n2cc(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(-n2c(C(=O)N(C)C)c(OCc3ccccc3)c(OCc3ccccc3)c2P(C)(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
lithium chloride complex (1.3 M in THF, 315 μL, 0.410 mmol) was added dropwise to a stirred solution of 3,4-bis(benzyloxy)-5-iodo-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (65) [prepared using the same procedure as Example S step (i) using (9) as starting material] (211 mg, 0.36 mmol) in THF (1.2 mL) at 0° C., the reaction mixture was allowed to stir for 15 min and isopropylmagnesium chloride. lithium chloride complex (1.3 M in THF, 100 μL, 0.13 mmol) was added, and the reaction mixture was allowed to stir for a further 15 min. A solution of dimethylphosphinic chloride (61 mg, 0.54 mmol) in THF (0.6 mL) was added and the reaction allowed to warm to RT and stirred for a further 16 h. The reaction mixture was quenched with 5% AcOH in MeOH (5 mL) and the volatiles removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-5% MeOH in DCM) to afford a crude residue. The crude residue was further purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 30-60% MeCN in water) to afford 3,4-bis(benzyloxy)-5-(dimethylphosphoryl)-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (66) (29 mg, 15%) as a colourless gum: m/z 533 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.44-7.28 (m, 12H), 6.92-6.87 (m, 2H), 5.22 (s, 2H), 5.05 (s, 2H), 3.82 (s, 3H), 2.76 (s, 3H), 2.63 (s, 3H), 1.41 (br d, J=13 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16](OC)=[O:17])[C:3]=1[CH2:20][CH3:21].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[C:3]=1[CH2:20][CH3:21]
Reactant: CCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCc1c(CO)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 88.1 %

Procedure:
Using methyl 5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.35 g) and a 1.5 mol/L solution (7.5 mL) of diisobutylaluminum hydride in toluene, a procedure as in Reference Example 5 was performed to give the title compound as a brown oil (yield 1.10 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13]Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19](NCC)[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][N:5]([CH2:4][CH2:3][C:19]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1)[CH3:8]
Reactant: Cn1ncc(Cl)c(NCCCCl)c1=O
Reactant: CCNc1cc(OC)c(OC)c(OC)c1
Product: COc1cc(CCN(C)CCCNc2c(Cl)cnn(C)c2=O)cc(OC)c1OC
Reaction time: 2.5 h
Yield: 34 %

Procedure:
On starting from 5-chloro-4-(3-chloropropylamino)-2-methyl-3(2H)-pyridazinone and 3,4,5-trimethoxyphenyl ethyl amine and proceeding according to method c) with the difference that melting is carried out at 140° C. for 2.5 hours the desired compound is obtained with a yield of 34%. Rf =0.6.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:52][C:51]4[CH:53]=[CH:54][C:48]([S:47][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=5)=[CH:49][CH:50]=4)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(Sc2ccccn2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Sc4ccccn4)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the mixture, and thionyl chloride (0.34 ml) was added to the mixture. The mixture was stirred at room temperature for 1 hour, and the mixture was added dropwise to the solution of 4-(2-pyridinylsulfanyl) aniline (0.53 g) and triethylamine (1.97 ml) in THF (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(2-pyridinylsulfanyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 182) (0.57 g).