Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=O)=O.O>CN(C=O)C>[CH2:42]([N:43]([CH2:46][CH3:47])[CH2:44][CH2:45][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=2)=[CH:21][CH:22]=1)[CH3:41]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Reactant: CCN(CC)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1
Temperature: 50 °C
Yield: 41.2 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(diethylamino)ethyl methanesulfonate (30 mg, 0.15 mmol). The mixture was heated at 50° C. for 15 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give 6-(4-(2-(diethylamino)ethoxy)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 8.06-7.90 (m, 4 h), 7.58 (s, 1H), 7.42 (t, 1H, J=7.6 Hz), 7.03-7.00 (m, 2H), 6.23 (d, 1H, J=7.2 Hz), 6.05 (d, 1H, J=8.1 Hz), 4.57 (brs, 2H), 4.27 (brs, 1H), 3.67 (brs, 1H), 3.52-3.41 (m, 3H), 3.22-3.20 (m, 4 h), 2.16-2.06 (m, 3H), 1.80 (brs, 1H), 1.45 (t, 6H, J=6.9 Hz), 1.28 (d, 3H, J=6.3 Hz). LC/MS: 486 [M+H]+, tR=1.12 min. HPLC: 98.72% at 214 nm, 99.10% at 254 nm, tR=5.46 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45]>>[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:45]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccc(Cl)c3)CN2C1=O
Yield: 96.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-chlorobenzoyl chloride (45 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 119 mg (94%) of 18-(3-chorobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.4% pure (HPLC), MS m/z 705 (M−H)−, HRMS: calcd. 707.2518 and found 707.2531 (M+H)+, mp 154-156° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:32][CH:33]3[CH2:35][O:34]3)[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3>C1COCC1.CCOC(C)=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:32][CH:33]([OH:34])[CH2:35][O:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7]3=[O:16])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCOCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
Sodium hydride dispersion (31.6 mg, 0.79 mmol) was added to a solution of N-(2-hydroxyethyl)-phthalimide (153.7 mg, 0.80 mmol) in anhydrous THF (1.2 ml, 0.67 M). The suspension is stirred for 15 minutes before the addition of carbazole epoxide 2-A. The reaction was stirred at room temperature for five minutes and then at 60° C. for 1 hour. The cooled reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted and the combined organics were filtered over a celite pad. The Crude product was used without further purification. Yield=44%
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[CH:4]=1.Cl.[NH2:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:32]([C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([NH:13][CH2:2][C:3]2[S:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[CH:4]=2)[CH:15]=1)=[O:34])([CH3:30])[CH3:31])#[N:33]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: BrCc1cc2nccnc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NCc1cc2nccnc2s1
Yield: 6.2 %

Procedure:
A solution of 6-(bromomethyl)thieno[3,2-b]pyrazine 47 (50 mg, 0.218 mmol), N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (72 mg, 0.218 mmol) and potassium carbonate (90 mg, 0.655 mmol) in acetonitrile (2 mL) was stirred overnight at 50° C. Water was added and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by HPLC gave the title compound 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(thieno[2,3-b]pyrazin-6-ylmethylamino)phenyl)benzamide 48 (6 mg, 6.23%). NMR (400 MHz, DMSO-d6) 1.71 (s, 6H), 2.16 (s, 3H), 4.72 (d, J=5.5 Hz, 2H), 6.02 (t, J=6.2 Hz, 1H), 6.98 (s, 2H), 7.08 (s, 1H), 7.54 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.92 (t, J=1.6 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 10.00 (s, 1H). (m/z)=442 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:8])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:18]1[C:19]([C:2]2[S:6][C:5]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[O:8])=[CH:4][CH:3]=2)=[CH:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1
Reactant: Cc1nc2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc2o1
Reactant: O=C(Nc1ccccc1F)c1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1nc2cc(Cl)c(-c3ccc(C(=O)Nc4ccccc4F)s3)cc2o1
Temperature: 110 °C
Yield: 39.1 %

Procedure:
A mixture of (5-bromo(2-thienyl))-N-(2-fluorophenyl)carboxamide (9) (24 mg, 0.08 mmol), 2-(5-chloro-2-methylbenzoxazol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) (23 mg, 0.08 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 12 mg) and sodium carbonate (32 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash column chromatography. The isolated crude product was re-purified on prep HPLC to furnish 12.1 mg of [5-(5-chloro-2-methylbenzoxazol-6-yl)(2-thienyl)]-N-(2-fluorophenyl)carboxamide (10) as white solid (yield: 39%; purity>95%). LC-MS: calcd. for C19H12ClFN2O2S: 387 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]([CH3:35])([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]1)[CH2:25][OH:26]>ClCCl>[CH3:23][C:24]([CH3:35])([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]1)[CH:25]=[O:26]
Reactant: CC1CCCC(CC(C)(C)CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1CCCC(CC(C)(C)C=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A solution of Dess Martin periodinane (9.0 g, 21.1 mmol, 1.3 eq) in dichloromethane (165 mL) was charged into a 250 mL three-necked round-bottom flask, equipped with a mechanical stirrer and a reflux condenser. The solution was cooled to 0° C. by the mean of an ice/salt bath. 2,2-dimethyl-3-(3-methylcyclohexyl)propan-1-ol (3.0 g, 16.3 mmol) was added dropwise. After stirring for 2 h at ambient temperature, the mixture was cooled down to −15° C. and the solid was filtered off. The organic solution was then concentrated. The resultant crude product was chromatographed on a silica gel column with 2% EtOAc in hexane as elution agent giving 2,2-dimethyl-3-(3-methylcyclohexyl)propanal (1.0 g, gc purity>85%; yield 33%).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6](=C)[CH2:7][S:8][C@H:3]12.CS(O)(=O)=[O:17]>CO>[NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:17])[CH2:7][S:8][C@H:3]12
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)O
Reactant: CS(=O)(=O)O
Solvent: CO
Product: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
7-Amino-3-methylenecepham-4-carboxylic acid (107 g.) was dissolved in a solution of methanol (6.4 l.) and methanesulfonic acid (57.7 g.). Ozone was bubbled into the solution at -70° to -75° C. until the starting compound was not detected. After bubbling nitrogen gas into the resultant mixture, sodium methoxide (3.5 g.) was added to the mixture below -65° C. Sodium borohydride (56.7 g.) was added to a solution of sodium hydroxide (14.4 g.) in water (3.2 l), stirred at room temperature for 20 minutes and chilled. The oxidized reaction mixture was added to the sodium borohydride solution over 3 minutes, and stirred at -4° to 0° C. for 20 minutes. The solution was adjusted to pH 4.0 with 6N hydrochloric acid, and allowed to stand at 5° C. overnight. The precipitates were collected by filtration, washed with methanol and then dried to give 7-amino-3-hydroxycepham-4-carboxylic acid (70.8 g.).
Reaction SMILES: [OH-].[Na+].[C:3]([N:13]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CCCC)=[O:19])[CH2:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]>CO>[C:3]([N:13]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: CCCCOC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 69.7 %

Procedure:
Aqueous 1M NaOH (6 ml) was added to a stirred solution of the above ester (1.37 g) in methanol (6 ml). After 1 hour, the methanol was evaporated. Water (20 ml) was added to the residue and 1M HCl (6 ml) was added dropwise to the stirred mixture. This aqueous phase was extracted with ethyl acetate (3×25 ml). The combined organic phases were washed with saturated brine (1×20 ml) dried and evaporated to give, as a colourless oil, N-Cbz-3-carboxy pyrrolidine (780 mg);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([O:9][CH3:10])[O:12][CH3:11])[CH:3]=1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(OC)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
Commercial 2-(3-Bromo-phenyl)-[1,3]dioxolane (1.3 mL, 8.64 mmol) was dissolved in anhydrous MeOH (40 mL) and catalytic amount of H2SO4 was added. The resulting reaction mixture was stirred 4 h at rt and finally extracted with petroleum ether (3×50 mL). The combined organic phases were washed with NaHCO3 (40 mL), dried (MgSO4), filtered and concentrated under vacuum to give 22b as a colourless oil (1.76 g, 88%), whose spectroscopic data were in close agreement with literature (29).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH3:15])[C:13](=[O:16])[C:12]([CH3:18])([CH3:17])[C:11]2=[O:19])[CH:7]=[C:6]([F:20])[C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[F:20][C:6]1[CH:7]=[C:8]([N:10]2[C@H:14]([CH3:15])[C@H:13]([OH:16])[C:12]([CH3:17])([CH3:18])[C:11]2=[O:19])[CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1cc(F)c(C#N)c(F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1cc(F)c(C#N)c(F)c1

Procedure:
Using 2,6-difluoro-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.539 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 67 mg, 67%).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])C(O)=O)=[CH:10][CH:9]=1)([OH:3])=O.ClCCl.FC(F)(F)[C:28]([O:30]C(=O)C(F)(F)F)=[O:29].Cl>O>[O:3]=[C:1]1[C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:18][C:28]([OH:30])=[O:29])=[CH:12][C:13]1=2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A stirred suspension of 4-(2-carboxybenzyloxy)phenylpropanoic acid (47.14 g, 0.157 mol) and dichloromethane (500 ml) was treated over 30 seconds with trifluoroacetic anhydride (75.61 g, 0.36 mol). The solid material slowly dissolved. The solution was heated 6 hours under reflux with exclusion of moisture. The cooled solution was treated with water (100 ml) and stirred 20 minutes at ambient temperature (mild exotherm). The mixture was strongly acidified with 5% hydrochloric acid and thoroughly agitated. The organic phase was washed with water (200 ml), dried (Na2SO4) and evaporated to dryness. Recrystallization from 65 ml of isopropanol afforded 35.3 g (79.6%) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-propanoic acid, m.p. 138.5°-139.5° C. The compound appeared pure and chromatographically identical with material which had previously been prepared according to procedure 6C below except that it is postulated that the product exists in two polymorphic forms and interconversion by partial melting followed by solidification to afford the higher melting form occurs at 128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C2CCCCO2)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10]1.O.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>CO>[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:40][CH:41]=1.[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:40][CH:41]=1.[F:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10]1
Reactant: CCCCCC#CCN1CC[C@@H](Nc2ncc(/C=C/C(=O)NOC3CCCCO3)cc2F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCCCC#CCN1CC[C@@H](Nc2ncc(/C=C/C(=O)NO)cc2F)C1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of (2E)-3-(5-fluoro-6-{[(3R)-1-(2-octyn-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (155 mg) in methanol (3.5 ml) was added 4-methylbenzenesulfonic acid hydrate (122 mg) at 25° C. and then stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was triturated with a mixed solvent of ethyl acetate, diisopropyl ether and methanol. Title compound (178 mg, 73%) was obtained as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=O.[CH2:34]1[N:39](P(Cl)(N2C(=O)OCC2)=O)[C:37](=O)OC1.C(N(CC)CC)C.CNC>ClCCl.C(#N)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)[C:14]1=[O:33])[C:10]([N:39]([CH3:34])[CH3:37])=[O:12]
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(F)cc1F
Agent: CNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 16 h

Procedure:
The acid (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid (0.747 g) prepared as described above was dried over P4O10 in vacuo for five hours to give 0.724 g drier material; this was dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylanne (0.223 ml) and BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 0.450 g) and the mixture was sonicated for ca. 1 min to give a gelatinous mass. After 10 minutes at room temperature a solution of dimethylamine in tetrahydrofuran (10 ml of 2M solution) was added to give a clear solution; this was left for 16 hours at room temperature. The solvents were removed under reduced pressure and the mixture was partitioned beween dichloromethane and 0.1M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified by flash column chromatography (12 g Biotage™ silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to give the (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide as a colourless solid 0.285 g.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[C:21]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Cc1cccnc1N
Product: Cc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-methylpyridine-2-amine as the starting materials.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([C:10](OC)=[O:11])=[N:6][S:7][C:8]=1[Cl:9]>C(O)C>[Cl:3][C:4]1[C:5]([CH2:10][OH:11])=[N:6][S:7][C:8]=1[Cl:9]
Reactant: COC(=O)c1nsc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nsc(Cl)c1Cl
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Add sodium borohydride (76 mg, 2.0 mmol) to methyl 4,5-dichloroisothiazole-3-carboxylate (212 mg, 1.0 mmol) in ethanol (10 mL) at room temperature and stir overnight. Add water, extract with dichloromethane three times. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give (4,5-dichloroisothiazol-3-yl)-methanol as a white solid (141 mg, 77%). 1H NMR (400 MHz, MeOH-d4) 4.66 (s, 2H).
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: OCc1ccccc1
Reactant: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of (93) (1.02 g, 3.34 mmol) in dichloromethane was added 1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for 30 min, benzyl alcohol (380 μL, 3.67 mmol) and 4-(dimethylamino)pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature of 16 h. After filtration, the filtrate was washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography of the residue on silica gel, eluting with 10% ethyl acetate/hexane, gave 820 mg (62%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.03 (d, J=6.4 Hz, 3H), 1.05(d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s, 2H), 5.49 (t, 1H), 6.32 (d, J=4.8 Hz), 1H), 7.34 (m, 5H). MS (ESI) m/z 396.24 (M+H+).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]([C:33]([O:35]C4C=CC=CC=4)=O)C(=O)OC4C=CC=CC=4)[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].[OH-:42].[Li+].Cl>CN(C)C=O.O1CCCC1.CO.O>[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:33](=[O:35])[NH:7][CH2:8][CH2:9][C:10]([OH:42])=[O:1])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: [OH-]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCCC(=O)O)c3)ccc21
Temperature: 25 °C
Yield: 66 %

Procedure:
Ethyl 4-aminopropionate hydrochloride (588 mg, 3.8 mmol) was suspended in N,N-dimethylformamide (3.0 ml), and then 5N aqueous solution of sodium hydroxide (0.77 ml, 3.8 mmol) was added, and the reaction mixture was stirred at room temperature. Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (400 mg, 0.77 mmol, Production example 5-2) was added thereto, and the reaction mixture was stirred at room temperature for 0.75 hours. Water was added to the reaction mixture, and this was subjected to extraction with ethyl acetate-tetrahydrofuran, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate) to yield a pale brown oil. This oil was dissolved in tetrahydrofuran (4.0 ml) and methanol (2.0 ml), 4N aqueous solution of lithium hydroxide (0.77 ml) was added at room temperature, and the reaction mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 1N hydrochloric acid (3.1 ml) was added while stirred at room temperature; and this was subjected to extraction with ethyl acetate-tetrahydrofuran, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A small amount of acetone was added to the obtained amorphous solid, and this solution was diluted with diethyl ether. The crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (200 mg, 0.50 mmol, 66%) as colorless crystals.