Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=[O:29])[CH:19]=1>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:28]([C:20]1[CH:19]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=1)=[O:29]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-bis(trifluoromethyl)-2-pyridinecarboxylic acid (Bionet Research) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown oil (66%). MS (ESI): m/z=440.12 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:28])[CH2:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22]COC)=[C:16]([O:26][CH3:27])[CH:15]=2)=[C:5]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:4]=1[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl.CO>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:28])[CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([O:26][CH3:27])[C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=2)=[C:5]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:4]=1[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Agent: Cl
Solvent: CO
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1cc(OC)c(O)c(OC)c1
Yield: 73.8 %

Procedure:
Then, 2.8 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone was dissolved in 4 ml of methanol, and 4 ml of hydrochloric acid/methanol was added to the solution and the mixture was heated and refluxed for 10 minutes. After the reaction, the solvent was removed from the reaction mixture by distillation, and the obtained solid was dissolved in a small amount of ethyl acetate and crystallized from diethyl ether/hexane to obtain 1.9 g (yield=75%) of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone in the form of a cotton-like crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][CH2:13]2)[N:7]=1
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 1 h

Procedure:
To 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (50 mg, 0.194 mmol) in DCM (2 mL) in ice bath was added DIEA (340 μl, 1.945 mmol) and methanesulfonyl chloride (16.67 μl, 0.214 mmol). The reaction mixture was stirred for 60 min. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. (30 mg, 46%). LCMS (m/z): 335.2/337.2 (MH+), 0.572 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[N:14]1[NH:15][C:16](=[O:20])[CH:17]=CC=1>>[O:20]=[C:16]1[NH:15][N:14]=[C:1]([C:4]2[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH:17]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1cccc(CC(=O)O)c1
Product: O=C(O)Cc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
5 g of 3-acetylphenylacetic acid (preparation described in Can. J. Chem.; 82; 12; 2004; 1760-1768) are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:15][N:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13]2[N:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[CH:17][N:18]=2)=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cn1
Temperature: 130 °C

Procedure:
A vial is charged with methyl 5-aminopicolinate 2 (0.83 mmol), 2-chloro-5-(4-methoxy-phenyl)-pyrimidine 3 (0.83 mmol), Pd(OAc)2 (0.124 mmol), xanthphos (0.124 mmol), Cs2CO3 (0.83 mmol) and anhydrous 1,4-dioxane (5 mL). The vial is evacuated and refilled with N2 twice and the mixture is heated in a microwave oven at 130° C. for 20 min. The vial is cooled to it and the reaction mixture is diluted with DCM, washed with 10% NH4Cl solution, brine and dried over Na2SO4. The solvent is removed in vacuum and the crude is triturated with EtOAc to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid methyl ester 4 as light brown solid. NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.93 (s, 2H), 8.83 (bs, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.08-7.06 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H). MS (m/z) (M+1)+: 337.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(Cl)cc1

Procedure:
4.02 g of 4-chlorobenzoyl chloride—prepared by reacting 4-chlorobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCCCN
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
12.5 g. (0.05 M) of Z-Pro-OH is converted to active ester as in Example 3 (a) and, with the addition of 5.7 ml. (0.06 M) of n-butylamine, it is stirred for 12 hours. The dioxane is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with 5% NaHCO3 and 1N-HCl, followed by drying. The ethyl acetate is distilled off under reduced pressure and, following the addition of petroleum benzin, the residue is filtered. The crude product is recrystallized from ethyl acetate. Yield 14.0 g. (92.7%); melting point: 94.0°-95.0° C, optical rotation [α]D21 -39.6° (c=0.54, in N,N-dimethylformamide)
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[N:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH3:2].[CH3:19][O:20][SiH:21]([O:24][CH3:25])[O:22][CH3:23]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[N:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][Si:21]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:19])[CH3:18]
Reactant: C=CCN(Cc1ccccc1)[Si](CC)(CC)CC
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)N(CCC[Si](OC)(OC)OC)Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 26.2 g (0.1 mol) of N-triethylsilyl-N-benzyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 12.2 g (0.1 mol) of trimethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 32.6 g of a fraction having a boiling point of 144-146° C./0.1 kPa.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Yield: 38.5 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 4-fluoro-2-methoxyphenylboronic acid (10 mg, 0.06 mmol) giving 8.3 mg (37%) of the title compound. MS (ESI+) calcd for C18H14FN5O3S2 431.052209, found 431.052249.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])([CH3:45])[CH3:43])=[O:5]
Reactant: CC(C)(O)CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), 4-amino-2-methylbutan-2-ol (12.92 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=34.1 min) to give (R/S)-2-hydroxy-N-(3-hydroxy-3-methylbutyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10.5 mg, 0.019 mmol, 26.9% yield): LCMS=517 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.65-7.77 (4 H, m), 7.54-7.66 (3 H, m), 5.10 (1 H, s), 3.32-3.42 (2 H, m), 1.62-1.78 (2 H, m), 1.22 (6 H, s). HPLC Peak RT=9.2 min (Analytical Method A).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][OH:17].NC1C=C(OC(C)C)C(C#N)=CN=1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCc1cccs1
Reactant: N#Cc1cnc(N)cc1F
Agent: CC(C)Oc1cc(N)ncc1C#N
Product: N#Cc1cnc(N)cc1OCc1cccs1

Procedure:
From intermediate 21 and thiophen-2-ylmethanol, synthesised in an analogous manner to intermediate 97, the title compound was obtained as a pale-yellow solid. (UPLC-MS 3) tR 0.75; ESI-MS 232.1 [M+H]+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:48])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[CH:33][C:32]=2[CH3:47])[CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH2:15]([O:14][C:12]([CH:11]=[C:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:48])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[CH:33][C:32]=2[CH3:47])[CH2:21][CH2:20][CH2:19]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To tetrahydrofuran (200 ml) is added sodium hydride (60%, 0.85 g), and thereto is added dropwise ethyl diethylphosphonoacetate (4.68 ml) with stirring under ice-cooling, and the mixture is further stirred under ice-cooling for 10 minutes. To the reaction mixture is added 5-oxo-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.10 g), and the mixture is stirred at room temperature for 6 hours. The reaction solution is poured into ice-water (200 ml), and extracted with ethyl acetate (300 ml). The extract is washed with brine (300 ml), dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane=1:2) to give 5-ethoxycarbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.22 g) in the form of a mixture of the E-type compound and the Z-type compound thereof, as colorless amorphous.
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH:19]=[CH:20][CH2:21]O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:5][CH2:21][CH:20]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:18][CH:17]=1
Reactant: OCC=Cc1ccc(-c2ccc(F)cc2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(C=CCCl)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.1 %

Procedure:
436 mg (3.8 mmol) of methanesulfonyl chloride were slowly added at room temperature to 513 mg (2.24 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)prop-2-en-1-ol and 679 mg (6.71 mmol) of triethylamine in 20 ml of dichloromethane. The mixture was stirred at room temperature for 6 h and extracted with a sodium hydrogencarbonate solution. The organic phase was evaporated to yield 550 mg of the title compound. MS: M+H+=248.1.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[OH-].[K+].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]1[C:25]2[C:20](=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[CH:22]=[C:23]([CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)[CH:24]=2)[CH2:19][N:18]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:17]1=[O:49]>CC#N.O.CS(C)=O.C(Cl)Cl>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:21]1[CH:22]=[C:23]([CH:26]2[CH2:31][CH2:30][C:29]3([O:32][CH2:2]3)[CH2:28][CH2:27]2)[CH:24]=[C:25]2[C:20]=1[CH2:19][N:18]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)[C:17](=[O:49])[N:16]2[C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C4CCC(=O)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C4CCC5(CC4)CO5)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 60 °C

Procedure:
To a suspension of trimethylsulfonium iodide (20 mg, 0.096 mmol) in CH3CN (0.3 mL) was added one drop of H2O followed KOH (s) (22 mg, 0.384 mmol). This mixture was heated at 60° C. for 10 min, then added 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-(4-oxocyclohexyl)-3,4-dihydroquinazolin-2(1H)-one (INTERMEDIATE 76) (40 mg, 0.064 mmol) in CH3CN (0.3 mL) and DMSO (0.2 mL) slowly. The reaction mixture was heated another 3.5 h, cooled to RT and diluted with CH2Cl2. It was washed with H2O followed by brine then dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography eluting with 1:3 acetone:hexane to give the title compound as a mixture of diastereomers. Mass spectrum (ESI): 633.2 (M+1).
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]c(Cl)nc12
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A solution of methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (prepared as described in US2009/186879) (2.0 g) in phosphoryl chloride (18 mL) was stirred at 120° C. for 2.5 hours. Excessive phosphoryl chloride was removed under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate under ice-cooling, and it was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography to obtain the titled compound (1.5 g) as white powder.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:7][C@@H:8]([C:18]([CH3:21])([CH3:20])[CH3:19])/[C:9](/[OH:17])=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Cc1ccccn1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](N)/C(O)=C/c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1(S)-tert-Butyl-2-oxo-3-pyridin-2-yl-propyl)-carbamic acid tert-butyl ester (300 mg, 1.0 mmol), was dissolved in dioxane saturated with HCl (20 mL) and the reaction mixture stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo to give the title compound as a yellow solid (0.37 g) which was used in Step C without further purification.
Reaction SMILES: [Na+:1].[CH2:2]([N+:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([CH3:24])([CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:5]=1/[CH:25]=[CH:26]/[CH:27]=[CH:28]/NC1C=CC=CC=1)[CH3:3].[Na].[C:37]([CH2:40][CH2:41][CH2:42][C:43]1([CH3:64])[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([S:52]([O-:55])(=[O:54])=[O:53])[CH:50]=2)[N+:45]([CH2:56][CH2:57][CH2:58][S:59]([OH:62])(=[O:61])=[O:60])=[C:44]1[CH3:63])([OH:39])=[O:38].N1C=CC=CC=1.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[Na+:1].[Na+:1].[C:37]([CH2:40][CH2:41][CH2:42][C:43]1([CH3:64])[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([S:52]([OH:55])(=[O:54])=[O:53])[CH:50]=2)[N:45]([CH2:56][CH2:57][CH2:58][S:59]([OH:62])(=[O:60])=[O:61])/[C:44]/1=[CH:63]/[CH:28]=[CH:27]/[CH:26]=[CH:25]/[C:5]1[C:6]([CH3:24])([CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([S:13]([OH:16])(=[O:14])=[O:15])[CH:8]=2)[N+:4]=1[CH2:2][CH3:3])([OH:39])=[O:38]
Reactant: CC1=[N+](CCCS(=O)(=O)O)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCC(=O)O
Reactant: CC[N+]1=C(/C=C/C=C/Nc2ccccc2)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC[N+]1=C(/C=C/C=C/C=C2/N(CCCS(=O)(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCC(=O)O)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Temperature: 25 °C

Procedure:
516 mg (1 mmol) 1-ethyl-3-methyl-2-((1E,3E)-4-phenylamino-buta-1,3-dienyl)-5-sulfo-3-(3-sulfo-propyl)-3H-indolium sodium salt and 483 mg (1 mmol) 3-(3-carboxypropyl)-2,3-dimethyl-5-sulfonato-1-(3-sulfopropyl)-3H-indolium sodium salt were dissolved in a mixture of 10 ml acetic acid and 10 ml acetic anhydride followed by the addition of 5 ml pyridine. The solution was stirred under reflux for 15 min. Twenty ml ether was added after cooling to room temperature. The obtained precipitate (mixture of the diastereomers OB-5a and OB-5b) was extracted by suction, washed with ether, and dried.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43]1>C(#N)C>[S:42]1[CH:46]=[CH:45][C:44]([S:47]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:49])=[O:48])=[CH:43]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccsc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 63.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0951 g, 0.206 mmol) was dissolved in acetonitrile (4.0 mL), and the solution was treated with triethylamine (0.0860 mL, 0.618 mmol) and 3-thiophenesulfonyl chloride (0.0754 g, 0.412 mmol) to obtain 4-(3-thiophenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0796 g, yield 64%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=CC=C[C:11]=2N=N1.[I:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][C:41](=O)[NH:40][N:39]=3)[CH:36]=2)[N:31]([S:44]([C:47]2[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH:30]=1.CC(N)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[I:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][C:41]([NH:8][CH:12]([CH3:13])[CH3:11])=[N:40][N:39]=3)[CH:36]=2)[N:31]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:51])=[CH:52][CH:53]=2)(=[O:45])=[O:46])[CH:30]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.4 %

Procedure:
BOP (253 mg, 0.571 mmol) was added to a stirred mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (250 mg, 0.519 mmol), propan-2-amine (0.13 mL, 1.56 mmol) and diisopropylethylamine (0.18 mL, 1.04 mmol) in DMF (1.5 mL). The reaction was stirred at RT for 14 h then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification on the ISCO (12 g column, 20-70% EtOAc in Hex) afforded 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (199 mg, 73%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 523.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (1H, d, J=8.6 Hz), 7.95 (1H, d, J=8.4 Hz), 7.86 (1H, s), 7.76-7.82 (2H, m), 7.71-7.76 (1H, m), 7.28 (2H, s), 4.54 (1H, d, J=7.6 Hz), 3.94-4.05 (1H, m), 2.37 (3H, s), 1.34 (6H, d, J=6.5 Hz).