Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: OC1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Br)ccc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (4 g, 19.28 mmol), tetrahydro-4-pyranol (2.20 ml, 23.13 mmol) and polymer supported triphenylphosphine (17.29 g, 39.29 mmol; purchased from Argonaut, loading 2.23 mmol/g) was suspended in DCM (250 ml) and then cooled to 0° C. Di-tert-butyl azadicarboxylate (6.65 g, 28.92 mmol) was added portionwise and the reaction mixture was warmed to r.t. and shaken for 2 h. The resin was filtered off and washed with DCM. The combined filtrates were evaporated to dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2%). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D27 as colorless oil (5.38 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[S:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(-c3ccccc3)sc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccccc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60% sodium hydride (69 mg, 1.73 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 40 minutes. The solution is cooled and 7-chloro-2-phenylthieno[3,2-b]pyridine-6-carbonitrile (270 mg, 1.0 mmol) is added. The reaction mixture is heated at reflux for 5.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The aqueous layer is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is treated with ethyl acetate and hexane and the insoluble material is collected by filtration. The solid is suspended in hot methanol and ethyl acetate and the mixture is filtered while warm to provide 50 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-phenylthieno[3,2-b]pyridine-6-carbonitrile as a light brown solid, mp 274–276° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.44–7.53 (m, 3H), 7.73 (d, J=7 Hz, 2H), 7.78 (s, 1H), 7.94 (s, 1H), 8.63 (s, 1H), 9.78 (s, 1H); MS 426.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:33][CH:30]1[CH2:31][CH2:32][N:28]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=4[N:18]([CH3:27])[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[N:5][CH:4]=2)[CH2:29]1
Reactant: OC1CCNC1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CN4CCC(O)C4)s3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.13 g) and 3-pyrrolidinol (60 mg) in N,N-dimethylformamide (8 ml) was added potassium carbonate (110 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (85 mg, yield 59%) as pale-yellow prism crystals. melting point 190-191° C. MS: 489(MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]([CH3:31])[CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCOCC3)n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-(methylsulfonyl)phenyl]-N-tetrahydro-2H-pyran-4-yl-6-(trifluoromethyl)pyrimidin-2-amine (0.05 g) in dry dimethylformamide (2 ml) was treated with sodium hydride (0.007 g, 60% in mineral oil) and the mixture stirred at ambient temperature for 30 minutes. Iodomethane (0.01 ml) was added and the mixture stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was purified by passing through a silica bond elute column and eluting with dichloromethane. Concentration of the eluent gave the title compound as a yellow solid (0.031 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (2.5 g, 16 mmol), N-methylpiperazine (2 mL, 18 mmol) and potassium carbonate (2.7 g, 19 mmol) in DMSO (7 mL) was stirred and heated at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (100 mL), washed with water (3×30 mL), brine, dried (MgSO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—40% methanol/dichloromethane (gradient) to afford the desired title compound as a yellow solid, 3.67 g, 97%.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[F:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[F:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: NCCCF
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Agent: Cl
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCCF)nn23)s1

Procedure:
Prepared as in example 5.6.3 from 1-[5-(6-fluoro-imidazo[1,2-b]pyridazine-3-yl)-thiophen-2-yl]-ethanone (50 mg, 0.2 mmol) and 3-fluoropropylamine hydrochloride [64068-31-1] (43 mg, 0.4 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 6H) 2.12-2.25 (m, 1H) 2.54 (s, 1H) 3.66-3.72 (m, 1H) 4.72 (t, J=5.51 Hz, 1H) 7.21 (s, 2H) 7.63-7.67 (m, 1H). LRMS (ESI) m/z 319.1 [(M+H)]+, calc'd for C15H15FN4OS: 318.38.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[CH3:33][CH2:34][N:35](C(C)C)C(C)C.BrCC#N>CN1C(=O)CCC1>[C:34]([CH2:33][N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)#[N:35]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CN1CCCC1=O
Product: N#CCN1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (85 mg, 0.18 mmol) was dissolved in 3 mL NMP with DIEA (95 μL, 0.54 mmol). To it was added bromoacetonitrile (36 μL, 0.54 mmol). The mixture was stirred at RT for 40 m and quenched with TFA. The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (75 mg). MS found for C26H26F2N6O as (M+H)+ 477.4. UV: λ=256 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.19-7.08 (4H, m), 5.82 (1H, s), 4.55 (2H, s), 4.43 (2H, s), 3.67 (2H, d, J=11.6 Hz), 3.23 (2H, t, J=12.0 Hz), 2.95 (1H, m), 2.19-2.03 (4H, m) ppm.
Reaction SMILES: [CH3:1][C:2]([O:16][C:17](=[O:24])[CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([N:19]([CH2:22][CH3:23])[C:18]1[C:17](=[O:24])[O:16][C:2]([CH3:15])([CH3:1])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CCN(CC)CC(=O)OC(C)(C)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Yield: 31 %

Procedure:
Sodium hydride, 60% dispersion (0.478 g, 11.96 mmol) was washed in hexane and suspended in DMF (5 mL). This suspension was added to a 0° C. solution of 2-(diethyl amino)acetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (1.70 g, 4.78 mmol) in DMF (20 mL). The resulting mixture was warmed to RT for 15 minutes. The mixture was diluted with ethyl acetate and quenched with water. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The residue was purified by swishing in ether/hexanes to give 500 mg of crystalline solid on filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc(Cl)cc1
Yield: 15 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 4-chlorobenzoyl chloride to afford the title compound (11 mg, 15%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=6.0 Hz), 6.91 (d, 1H, Harom, J=8.0 Hz), 7.42 (t, 1H, Harom, J=8.0 Hz), 7.59-7.63 (m, 3H, Harom), 7.65 (d, 1H, Harom, J=8.0 Hz), 7.80 (d, 1H, HPy,6, J=6.0 Hz), 7.96 (d, 2H, Harom, J=9.0 Hz), 10.40 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C19H14N4O3Cl: 381.0754; found: 381.0753.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2][NH:1][C:30](=[O:31])[O:32][CH3:33])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Of the compound from Example 101A, 500 mg (1.64 mmol) were introduced in dichloromethane together with 320 μl (2.30 mmol) of triethylamine, with ice cooling, and 152 μl (1.97 mmol) of methyl chloroformate were added. The ice bath was removed and the mixture was stirred for a further 1 h. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. The product fractions were combined and freed from the solvents on a rotary evaporator, and the residue was dried in an HV. This gave 428 mg (72% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([OH:8])=O)=[N:2]1.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(N(C(C)C)C(C)C)C.[F:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][C:48]=1[C:49]1[C:50]([C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)=[N:51][C:52]([NH2:56])=[C:53]([NH2:55])[CH:54]=1>CN(C=O)C>[NH2:56][C:52]1[N:51]=[C:50]([C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)[C:49]([C:48]2[CH:47]=[CH:46][N:45]=[CH:44][C:43]=2[F:42])=[CH:54][C:53]=1[NH:55][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:8]
Reactant: O=C(O)c1nc[nH]n1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)c1nc[nH]n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.1 %

Procedure:
A solution of 1H-1,2,4-triazole-3-carboxylic acid (0.072 g, 0.64 mmol), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (0.243 g, 0.64 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.17 mmol) in DMF (1.5 mL) was stirred for 15 minutes under argon. Finally, 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.15 g, 0.53 mmol) in DMF (3 mL) was added and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the crude mixture was purified by silica gel flash chromatography (90:10 dichloromethane/methanol) to give the title compound (0.070 g, 35% of yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH3:18])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:18][Br:20])[CH3:2]
Reactant: CCOC(=O)c1cccc(Oc2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(Oc2ccccc2)c1CBr
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 2-methyl-3-phenoxy-benzoic acid ethyl ester (5.23 g, 0.02 mol), N-bromosuccinimide (3.82 g, 0.02 mol) and benzoyl peroxide (247.5 mg, 1.1 mmol) in carbon tetrachloride (80 mL) was refluxed for 4 h before it was cooled to room temperature and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (7.08 g): 1H NMR (CDCl3, 200 MHz): δ=7.66 (m, 1H), 7.24 (m, 3H), 7.03 (m, 1H), 6.98 (m, 3H), 5.09 (s, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]2[O:14][C:13]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[OH:24][CH:21]([CH2:20][O:19][C:18]1[C:25]([CH3:27])=[CH:26][C:15]([C:13]2[O:14][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[N:11][N:12]=2)=[CH:16][C:17]=1[CH3:28])[CH2:22][O:23][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)COS(C)(=O)=O
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of 3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (627 mg, 1.56 mmol) and DIPEA (311 mg, 2.41 mmol) in DCM (10 mL), methanesulfonyl chloride (207 mg, 1.81 mmol) is added. The mixture is stirred at rt before another portion of DIPEA (40 mg, 0.31 mmol) and methanesulfonyl chloride (36 mg, 0.31 mmol) is added. Stirring is continued for 1 h before the reaction is quenched by adding water. The mixture is extracted with DCM. The org. extract is washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give methanesulfonic acid 2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl ester (220 mg) as a colourless oil; LC-MS: tR=1.08 min, [M+1]+=481.09.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]([SH:12])=[N:6][C:7]([SH:11])=[N:8][C:9]=1[NH2:10].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.O>CO>[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:11][C:7]1[N:8]=[C:9]([NH2:10])[C:4]([NH2:3])=[C:5]([S:12][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[N:6]=1
Reactant: Nc1nc(S)nc(S)c1N
Reactant: Fc1cccc(CBr)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc(SCc2cccc(F)c2F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of potassium hydroxide powder (7.72 g) in methanol (250 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (10.9 g) followed by 2,3-difluorobenzyl bromide (22.5 g). The reaction mixture was stirred for one hour at room temperature then poured into water (500 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropanol and diethyl ether, to give the subtitled compound as a pale brown solid (15.0 g).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21][N:20]=2)=[CH:14][C:10]=1[C:11]([OH:13])=O.Cl.[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:11]([C:10]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:9]=3)[CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[NH:21][N:20]=3)=[O:13])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CCC(OC2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 39.2 %

Procedure:
Triethylamine (0.298 ml, 2.14 mmol) was added in one portion to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (200 mg, 0.71 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (121 mg, 0.71 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (352 mg, 0.93 mmol) in DMA (2 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (120 mg, 39% yield); 1H NMR (400.132 MHz, DMSO) δ 1.22-1.86 (11H, m), 3.00-3.20 (2H, m), 3.25-3.43 (2H, m), 3.52-3.56 (1H, m), 3.91-4.05 (2H, m), 4.35 (2H, s), 7.20 (1H, d), 7.31 (1H, s), 7.34-7.40 (2H, m), 7.80-7.89 (2H, m), 7.96 (1H, d), 8.26 (1H, d), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=2.18 (M+H 432.1)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.45 g, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.16 g, 0.9 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 195 mg, 35%). MS (H+), 628.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[CH:37]=[CH:36][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:36][CH:37]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 80 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide (Intermediate 29, 100 mg) in chloroform (4 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (0.5 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.