Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=1)=O.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].C([SiH](CC)CC)C>O>[F:17][C:18]([F:23])([F:22])[C:19]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=1)=[O:20]
Reactant: O=C(CCCBr)c1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O
Product: O=C(OCCCCc1ccc2[nH]c(=O)oc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 100 ml three-necked round-bottomed flask equipped with dropping funnel, thermometer, and N2 inlet were added 10 g (0.035 mol) 6-(4-bromobutyryl)-benzoxazolone and 26.08 ml (0.35 mol) trifluoroacetic acid. To the stirring suspension was added dropwise 12.93 ml (0.080 mol) triethylsilane, and the reaction stirred at room temperature for 16 hours. The reaction was then poured into water, and the resulting white solid filtered and washed with water. It was then suspended in isopropyl ether, stirred, and filtered to afford white solid 6-(4-trifluoroacetoxybutyl)-benzoxazolone, m.p. 100°-103° C., 10.47 g (98.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=S)[S:10]C)[CH2:4][O:3]1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=[S:10])[NH:15][NH2:16])[CH2:4][O:3]1
Reactant: CSC(=S)NCC1COC(C)(C)O1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1(C)OCC(CNC(=S)NN)O1
Yield: 69.4 %

Procedure:
A misture of methyl N-(2,2-dimethyl-dioxolan-4-yl-methyl)-dithiocarbamate (23,6 g) prepared according to U.S. Pat. No. 4,064,242, absolute ethanol (500 cc) and hydrazine hydrate (5.6 g) is heated under reflux for 2 hours 30 minutes. It is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in diethyl ether (100 cc). After filtration and drying, 4-(2,2-dimethyl-dioxolan-4-yl-methyl)-thiosemicarbazide (15.2 g) is obtained in the form of a cream-coloured solid melting at 145° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[C:3]=1[F:10].[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.[F-].[K+]>C(#N)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:17]2[C:12]([F:11])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[F:10]
Reactant: Nc1cnc(Cl)c(F)c1I
Reactant: OB(O)c1cccnc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Nc1cnc(Cl)c(F)c1-c1cccnc1F
Temperature: 90 °C
Yield: 75.2 %

Procedure:
A degassed mixture of 6-chloro-5-fluoro-4-iodopyridin-3-ylamine (98.7 g, 362 mmol), 2-fluoropyridine 3-boronic acid (68.3 g, 485 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.7 g, 10.9 mmol) and potassium fluoride (63 g, 1.09 mol) in a mixture of acetonitrile (900 mL) and water (275 mL) was heated at 90° C. for 2 hours. The reaction mixture was allowed to cool to ambient temperature and filtered through Celite© and washed through with ethyl acetate. The filtrate was diluted with ethyl acetate and the organic layer collected, dried (Na2SO4), filtered and concentrated in-vacuo to afford a residue. The resultant residue was triturated with diethyl ether to afford the title compound as a grey solid (65.8 g, 75%). The trituration liquors were concentrated and purified by flash chromatography (silica: dichloromethane to 20% ethyl acetate/dichloromethane) to afford, after trituration with ether, an additional batch of the title compound as a grey solid (9.7 g, 11%). Total yield=75.5 g, 86%. 1H NMR (400 MHz, CDCl3): 8.39 (ddd, J=4.9, 2.0, 1.1 Hz, 1H), 7.86-7.84 (m, 2H), 7.39 (ddd, J=7.4, 4.9, 1.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24](O)=[O:25].Cl.[OH:28][C:29]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:29]=2[OH:28])[CH2:34]1)=[O:25]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 18.6 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 103 (18.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.82 and 2.91 (2t, 2H), 3.56 and 4.02 (2t, 2H), 3.74-3.80 (m, 6H), 3.86 and 3.91 (2s, 6H), 4.45 and 4.90 (2s, 2H), 6.33-6.91 (m, 2H), 7.62-7.86 (m, 3H), 8.00-8.06 (m, 1H), 8.21-8.28 (m, 1H), 8.70 and 8.73 (2s, 1H); MS (ESI) m/z 520 ([M+H]+).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH3:16][Si:17]([CH3:24])([CH3:23])[NH:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>>[CH3:16][Si:17]([N:18]([Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C

Procedure:
Cytosine (12.0 g), hexamethyldisilazane (60 ml) and ammonium sulfate (10 mg) were refluxed at 125° C. for 30 minutes to form a homogenous solution. The hexamethyldisilazane was removed by distillation to form the titled product.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:12][NH2:13]>CO>[CH3:2][C:1]1[C:4]2[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=2[NH:13][N:12]=1
Reactant: CC(=O)C1C(=O)CCCC1=O
Reactant: NN
Solvent: CO
Product: Cc1n[nH]c2c1C(=O)CCC2
Temperature: 0 °C

Procedure:
To an ice-cold solution of 33.3 grams of 2-acetyl1,3-cyclohexanedione in 400 ml of methanol was added dropwise a solution of 7.2 ml of hydrazine in 50 ml of methanol and the resulting reaction mixture was heated at reflux for 20 hours. The solvent was then removed under reduced pressure and the residue was triturated in ethyl ether to give 1,5,6,7-tetrahydro-3-methyl-4H-indazol-4-one as a yellow crystalline solid melting at about 154°-157° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][N:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][N:5]([CH:8]([CH3:12])[C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 75 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 137 mg (75%) of the title compound as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.43 (m, 2H), 7.15 (m, 2H), 5.52 (q, J=7.0 Hz, 1H), 3.75 (m, 1H), 3.41 (m, 1H), 2.81 (m, 2H), 2.28 (s, 3H), 1.85-1.99 (m, 2H), 1.81 (d, J=7 Hz, 1H); MS: (ES) m/z calculated for C20H19ClF4N5O [M+H]+ 456.1, found 456.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([Cl:21])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(c(C(=O)O)c1OC)CCCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(c(C(=O)Cl)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[CH:31][CH:32]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCC/C=C/CO
Reactant: CCCCCCc1ccc(-c2ccc(-c3ccc(O)s3)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2ccc(-c3ccc(CCCCCC)cc3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
Triphenylphosphine (1.4 g) is added in small portions to a solution of (E)-hex-2-en-1-ol (0.60 g), 2-hydroxy-5-(4′-hexylbiphenyl-4-yl)thiophene (0.50 g), diethylazodicarboxylate (0.80 g) in dry tetrahydrofuran (100 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.12 g of 2-[(E)-hex-2-enyloxy]-5-(4′-hexylbiphenyl-4-yl)thiophene.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][N:7]([CH3:20])[C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reaction time: 72 h
Yield: 61.2 %

Procedure:
To a mixture of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (50 mg, 0.137 mmol) and potassium carbonate (76 mg, 0.548 mmol) in DMF (2 mL) was added iodomethane (26 μL, 0.411 mmol) at RT. After 3 days, the reaction mixture was partitioned between ethyl acetate and water. The resultant biphasic mixture was separated, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was crystallised from ethyl acetate to give the title compound (31.8 mg, 61%) as a cream solid. The mother liquors were evaporated, the residue was dissolved in DCM and subjected to flash chromatography (SiO2, gradient 70 to 100% ethyl acetate in cyclohexane) to afford a further quantity of the title compound (17.6 mg, 34%). LCMS (Method A): RT=3.78 min, [M+H]+=380.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]1([C:12]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:16][CH:15]=2)=[O:13])[S:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[S:3]1[CH2:4][CH2:5][N:6]=[C:2]1[NH:1][C:19](=[O:20])[CH:18]([C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[C:7]2[S:11][CH:10]=[CH:9][CH:8]=2)=[CH:24][CH:23]=1)[CH3:22]
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Reactant: NC1=NCCS1
Solvent: C1COCCO1
Product: CC(C(=O)NC1=NCCS1)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred and refluxing solution of 3.06 parts of 2-amino-2-thiazoline in 60 parts of dioxane is added a solution of 4.2 parts of p-(2-thenoyl)hydratropoyl chloride in 45 parts of dioxane. Upon completion, stirring at reflux is continued for 30 minutes. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol, yielding N-(2-thiazolin-2-yl)-p-(2-thenoyl)hydratropamide; mp. 186.4° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=O)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH2:14][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCc1c(F)cnc2ccc(=O)n(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Reaction time: 3 h
Yield: 77.9 %

Procedure:
(8-Ethyl-7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (0.168 g, 0.718 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (0.172 g, 0.860 mmol) was dissolved in CHCl3 (6 ml) and MeOH (0.6 ml) at rt under argon, whereupon NaBH(OAc)3 (0.497 g, 2.34 mmol) was added, after which it was stirred for 3 h. The reaction was then purified by chromatography on silica gel using a 0-20% MeOH in EtOAc gradient to give the title compound as a yellow oil (0.234 g, 72%).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.O>O1CCCC1>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([B:1]([OH:6])[OH:2])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:25][CH2:26]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Temperature: -78 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
Triisopropyl borate (0.64 mL, 2.8 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.602 g, 1.9 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (7 mL) at −78° C. under a nitrogen atmosphere followed by dropwise addition of n-butyllithium (1.4 mL, 2.2 mmol). The resulting mixture was stirred at −78° C. for 2 h and at room temperature for another 16 h. Water (2.0 mL) was added and the mixture stirred for 30 min and evaporated to dryness. The residue was pre-adsorbed onto silica and purified by column chromatography using methylene chloride/methanol, (9:1 to 1:9), as the eluent. The product was re-crystallized from water to give 311 mg (58% yield) of the title compound as white crystals: mp 215-218° C.; 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br s, 1H), 8.47 (br s, 2H), 8.05 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 3.77 (m, 2H), 3.40 (m, 2H), 3.13 (m, 2H), 2.71 (s, 3H), 2.65 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 133.7, 133.3, 124.7, 49.8, 41.6, 41.4; MS (TSP) m/z 285 (M++1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([OH:59])=O)[NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH2:60][CH2:61][CH:62]([OH:65])[CH2:63][OH:64]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][CH2:45][CH2:46][CH2:47][C@H:48]([NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[C:57]([NH:60][CH2:61][CH:62]([OH:65])[CH2:63][OH:64])=[O:59])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCC(O)CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
658.5 mg (1.8 mmol) of HATU and 129.2 mg (1 mmol) of N,N-diisopropylethylamine are added to a solution of 366 mg (1 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 182.2 mg (1 mmol) of 3-aminopropane-1,2-diol are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: Cl.[N:2]1([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:7][CH2:6][C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].Cl>C(Cl)Cl>[CH3:40][S:41]([N:9]1[CH2:8][C:5]2([CH2:6][CH2:7][N:2]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1ccccc1C(F)(F)F)N1CCC2(CC1)CNCc1ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of (E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one HCl salt (40 mg, 0.09 mmol) in CH2Cl2 (4 mL) was treated with i-Pr2NEt (0.05 mL, 0.28 mmol) and MeSO2Cl (0.014 mL, 0.18 mmol). The mixture was stirred overnight at rt and applied to a 10-mL Chem-Elut cartridge that had been wetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford (E)-1-(2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (20 mg, 45%). 1H NMR (CDCl3) 1.77 (m, 1H), 1.88 (m, 1H), 2.04 (m, 1H), 2.13 (m, 1H), 2.92 (s, 3H), 3.00 (m, 1H), 3.23 (m, 1H), 3.47 (m, 1H), 3.90 (m, 1H), 4.02 (m, 1H), 4.37 (m, 1H), 4.59 (m, 1H), 4.78 (d, 1H), 6.82 (d, 1H), 7.05-7.75 (8H), 7.99 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][CH:36]([CH3:41])[CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)CC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 3-methylbutyric acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(3-methyl-butyrylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:44][N:45]1[C:49]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=3[O:56][C:57]3([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)[C:48]=2[CH:47]=[N:46]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:60]2[CH2:61][CH2:62][C:57]3([C:48]4[CH:47]=[N:46][N:45]([CH3:44])[C:49]=4[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=4[O:56]3)[CH2:58][CH2:59]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask was added 4-bromo-3-methoxy-benzoic acid (860 mg, 3.7 mmol), HATU (1.4 g, 3.7 mmol), DMF (6 mL) and triethylamine (1.4 mL, 10 mmol). The reaction mixture was allowed to stir for 10 minutes. 1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (860 mg, 3.4 mmol) dissolved in DMF (6 mL) was added, and the mixture was allowed to stir at 25° C. After 2 h, the reaction was quenched with brine and was extracted with ethyl acetate. The combined organic layers were washed with brine 3 times. The combined organic layer were dried over sodium sulfate and evaporated. The residue was purified via silica gel chromatography (5-90% EtOAc:hexanes) to give (4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone as white foam. ESI-MS m/z calc. 467.1. found 468.2 (M+1)+. Retention time: 3.04 minutes (4 min run).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:24]1([C:34]2[N:39]=[N:38][N:37]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([O:46]CCO)=[CH:42][C:41]=3[OH:50])[C:35]=2[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([C:34]2[N:39]=[N:38][N:37]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:42][C:41]=3[OH:50])[C:35]=2[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1

Procedure:
9.11 g of acetic anhydride, 18.1 g of triethylamine and 0.73 g of dimethylaminopyridine in 400 ml of anhydrous dichloromethane are added to the product from Example A9. The reaction mixture is heated to boiling. When the reaction is complete (monitoring by TLC), the solvent is removed in vac. and the residue is taken up in dichloromethane. The organic phase is washed with water and dried with magnesium sulfate. After removal of the solvent, the residue is chromatographed on silica gel, yielding the product having the following NMR data: