Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1cccc(-c2cc(N)ncn2)c1
Temperature: 125 °C
Yield: 69.6 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-methoxyphenylboronic acid (0.475 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.035 g, 0.050 mmol) was suspended in DME/EtOH/water (15:2:3 mL), heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60% ethyl acetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g, 1.74 mmol, 70% yield) as an off-white solid. LCMS R.T.=1.28; [M+H]+=201.98.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[C:11]1([N:17]2[C:21]3[C:22]4[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=4[S:24][CH2:25][C:20]=3[C:19]([C:30](Cl)=[O:31])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CN(C)C=O>[C:1]([CH:3]([C:30]([C:19]1[C:20]2[CH2:25][S:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:21]=2[N:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:18]=1)=[O:31])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=C(Cl)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Temperature: 25 °C
Yield: 59.6 %

Procedure:
Ethyl cyanoacetate (1.4 g) is treated with 50% sodium hydride (0.58 g) in dimethylformamide (10 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride (3.26 g), prepared according to Example 5, dissolved in dimethylformamide (10 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 20 hours, then it is diluted with ice water and acidified to pH 3 with 37% HCl. The precipitate is extracted with ethyl acetate and the organic solution washed with water and then evaporated to dryness in vacuo. The residue is purified over a SiO2 column, using hexane-ethyl acetate 80:20 as eluent, to give 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoic acid, ethyl ester (2.4 g), m.p. 176°-178° C., which is reacted with aniline (1.7 g) in xylene (100 ml) at the reflux temperature for 48 hours. After cooling the precipitate is filtered and washed with xylene, then crystallized from dichloromethane/methanol to give 1.5 g of 2 -cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 228°-230° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[C:11]([CH3:17])[CH:10]=2)[S:5][C:6]=1[Cl:7].CO[CH:20](OC)[N:21]([CH3:24])[CH2:22][CH3:23].C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([N:13]=[CH:20][N:21]([CH2:22][CH3:23])[CH3:24])=[C:11]([CH3:17])[CH:10]=2)[S:5][C:6]=1[Cl:7]
Reactant: Cc1cc(Oc2nc(Cl)c(Cl)s2)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(Cl)c(Cl)s2)cc1C
Temperature: 105 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
To a mixture of 2.0 g (6.9 mmol) of 4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylaniline in 2.5 ml toluene a solution of 9.7 mmol of N-(dimethoxymethyl)-N-methylethanamine (60% in methanol) was added. The reaction mixture was stirred for 16 hrs at 105° C. The reaction mixture was concentrated in vacuo. Column chromatographie (gradient: cyclohexane->ethyl acetate) yielded 2.4 g (6.7 mmol) 97% of N′-{4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=2.04
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=4[N:14](C(C)=C)[C:13]3=[O:25])[CH:10]=1)[N:7]([CH3:26])[C:6]([CH3:27])=[C:5]2[CH3:28].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=4[NH:14][C:13]3=[O:25])[CH:10]=1)[N:7]([CH3:26])[C:6]([CH3:27])=[C:5]2[CH3:28]
Reactant: C=C(C)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)[nH]c(=O)n2Cc1cc(Cl)cc2c(C)c(C)n(C)c12
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a solution of 1-(5-Chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-3-isopropenyl-5-methyl-1,3-dihydro-benzimidazol-2-one (60 mg, 0.15 mmol) in a mixture of MeOH (3 mL) and water (3 mL), was added 1N HCl (2 mL). The reaction mixture was heated to 60° C. for 2 h. When the reaction was completed, the mixture was extracted with CH2Cl2 (×2). The organic phase was dried over Na2SO4 and concentrated to afford 40 mg of the desired product. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:28]4[C:27]([Cl:26])=[CH:32][CH:31]=[C:30]([C:33]#[N:34])[CH:29]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cl)c(B(O)O)c1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cc(C#N)ccc2Cl)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with (2-chloro-5-cyanophenyl)boronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 3′-(1-benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl)-6-chloro-biphenyl-3-carbonitrile as a light yellow oil. MS: 480.0 ([M+H]+)
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][OH:13])=[N:4]1)[CH3:2].C[N+]1([O-])CCOCC1.C(#N)C>CC(O)C>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]=[O:13])=[N:4]1)[CH3:2]
Reactant: CCn1cc2c(CO)cccc2n1
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CC(C)O
Product: CCn1cc2c(C=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
(2-Ethyl-2H-indazol-4-yl)methanol (1.14 g, 6.47 mmol), 4 Å molecular sieves (550 mg), 4-methylmorpholine N-oxide (1.89 g, 16.2 mmol) and tetra-n-propylammonium perruthenate(VII) (114 mg, 0.323 mmol) were added to acetonitrile (70 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. 2-Propanol was added, and the mixture was stirred for 30 min. The mixture was filtered by silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (820 mg, yield 73%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.I[CH:16]([CH3:18])[CH3:17]>>[CH:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)([CH3:18])[CH3:17]
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Reactant: CC(C)I
Product: CC(C)Oc1ccc2c(c1)C(=O)OC(C)(C)O2

Procedure:
The title compound was prepared from 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (example 38-a) and 2-iodopropane under conditions analogous to experimental example 38-b, to give the desired product as a white solid. MS: (+) m/z 237.12 (M+1)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][CH:29]=[C:17]([Cl:16])[CH:18]=1)[CH2:25][CH3:26]
Reactant: NCc1ccccn1
Reactant: CCC(Oc1cccc(Cl)c1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(Oc1cccc(Cl)c1)C(=O)NCc1ccccn1
Reaction time: 4 h
Yield: 62.9 %

Procedure:
In 50 ml of toluene were dissolved 1.6 g (0.012 mole) of 2-aminomethylpyridine and 1.2 g (0.012 mole) of triethylamine, and thereto was added dropwise a solution 2.8 g (0.012 mole) of 2-(3-chlorophenoxy)-butyroyl chloride in 20 ml of toluene at room temperature with stirring. After the reaction was carried out for 4 hours, the reaction mixture was washed with water, dilute aqueous sodium hydroxide and then water successively. After the toluene layer was dried, the toluene was removed by distillation. The thus obtained oil was subjected to column chromatography to give 2.3 g of N-(2-pyridylmethyl)-2-(3-chlorophenoxy)-butyramide showing nD26 1.5610 as pale yellow oily liquid.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([C@H:35]2[N:39](C(OC(C)(C)C)=O)[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([C@@H:35]2[CH2:36][CH2:37][C:38]([CH3:47])([CH3:48])[NH:39]2)[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4)CC3)c21
Reaction time: 8 h
Yield: 79 %

Procedure:
4M HCl in dioxane (6 mL, 24 mmol) was added to a solution of (S)-tert-butyl 5-((S)-1-(3-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.020 g, 0.034 mmol) in dry DCM (15 mL) and stirred overnight. The solvent was evaporated to dryness to reveal (S)-2-(3-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.015 g, 0.027 mmol, 79% yield). HPLC, 220 nm, retention time=1.91 minutes, 92% purity. LC/MS, retention time=2.15 minutes, (APCI+) m/z=484 [M+H]+. 1H NMR (400 MHz, D2O) 8.35 (s, 1H), 7.35-7.28 (m, 3H), 7.25-7.15 (m, 1H), 5.22 (t, J=8.20 Hz, 1H), 4.28-4.00 (m, 2H), 3.88-3.71 (m, 1H), 3.67-3.55 (m, 1H), 3.55-3.42 (m, 4H), 3.36-3.05 (m, 1H), 2.16 (dd, J1=7.81 Hz, J2=13.27 Hz, 1H), 2.10-1.93 (m, 1H), 1.88-1.70 (m, 4H), 1.36 (s, 3H), 1.30 (s, 3H), 0.94 (d, J=7.03 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[N:18]=5)=[CH:14][C:9]=4[N:8]=[C:7]3[C@@H:27]3[C@H:29]([C:30]([OH:32])=[O:31])[C:28]3([CH3:36])[CH3:35])[CH:3]=2)=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccc(F)cc3)c2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 4-fluorophenylboronic acid in Step A. MS (ESI): mass calcd. for C36H30FN3O3, 571.23; m/z found, 572.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=8.5, 1H), 8.12 (d, J=8.5, 1H), 7.86 (d, J=8.2, 1H), 7.80-7.74 (m, 1H), 7.71 (d, J=8.4, 1H), 7.61-7.55 (m, 1H), 7.54-7.50 (m, 1H), 7.46-7.39 (m, 3H), 7.37-7.34 (m, 1H), 7.33-7.30 (m, 1H), 7.29-7.26 (m, 1H), 7.17-7.08 (m, 3H), 7.01-6.97 (m, 1H), 5.54-5.37 (m, 4H), 2.34-2.30 (m, 1H), 2.15 (d, J=8.2, 1H), 1.18 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.[NH2:21][C@@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[CH:31]([NH:30][C:28]([C@H:25]1[CH2:24][CH2:23][C@@H:22]([NH:21][C:2]2[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH2:27][CH2:26]1)=[O:29])([CH3:33])[CH3:32]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCCC2)cc1F
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
To a solution of 1-(2-(3-fluoro-4-nitrophenoxy)ethyl)piperidine (220 mg, 0.820 mmol) and cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (190 mg, 0.861 mmol) in ACN (0.8 mL) was added DIPEA (0.301 mL, 1.722 mmol). The mixture was heated at 80° C. in a sealed tube for 14 hours, and then additional cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (38 mg, 0.172 mmol) and DIPEA (0.100 mL, 0.574 mmol) were added. The resulting mixture was heated an additional 24 hours. The mixture was diluted with DCM (5 mL), washed with water/brine mixture, brine, and the organic layer was dried over Na2SO4, filtered and evaporated to afford cis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide.
Reaction SMILES: [C:1]1(=[O:35])[N:5]([C@@H:6]2[C:28](=[O:29])[N:8]3[CH:9]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)=[O:16])[C:10]([CH3:14])([CH3:13])[S:11](=[O:12])[C@H:7]23)[C:4](=[O:30])[C:3]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:2]12.[Cl:36]N1C(=O)CCC1=O>ClCCCl>[CH3:13][C:10](=[CH2:14])[CH:9]([N:8]1[C:28](=[O:29])[CH:6]([N:5]2[C:4](=[O:30])[C:3]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:2]3[C:1]2=[O:35])[CH:7]1[S:11]([Cl:36])=[O:12])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2S1=O
Solvent: ClCCCl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Cl

Procedure:
A solution of 49.7 g. (0.1 mol) p-nitrobenzyl 6β-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 13.4 g. (0.1 mol.) of N-chlorosuccinimide in 1.5 L. of 1,2-dichloroethane was refluxed for 70 minutes. The mixture was cooled, washed with water and brine, and then dried over MgSO4. The solvent then was evaporated, and the residue was dried in vacuo for 3 hours to obtain 52.0 g. of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][N:17]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([C:19]1[O:18][N:17]=[C:16]([NH:15][C:12]([C@@H:9]2[CH2:10][CH2:11][N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:14])[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(O)[C@@H]1CCN1c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold solution (0° C.) of (S)-1-(4-Chloro-phenyl)-azetidine-2-carboxylic acid (100 mg; 0.472 mmol) and 3-amino-5-t-butylisoxazole (66 mg; 0.472 mmol) in pyridine (1.5 mL) is added phosphorus oxychloride (0.043 m; 0.48 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is diluted with ethyl acetate and washed with diluted NH4Cl aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, m/z 334 [M+H+].
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH:23]=[CH:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)C.ICI.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][C@@H:23]2[C@@H:22]([CH2:33]2)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1C=CCC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ICI
Product: CC(C)(C)OC(=O)N1[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]2C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (3.6 g, 8.0 mmol) in DCM (40 mL) was added a 1 M solution of diethylzinc (9.0 mL) followed by diiodomethane (3.2 g, 12.0 mmol) over 15 min. The reaction mixture was stirred for 30 min at 0° C., warmed to RT and stirred for 3 h. The pH of the reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, purified by silica gel chromatography (eluting with 0-15% EtOAc in petroleum ether) and combined with the product of a similar run to provide the title intermediate (4.5 g) as a colorless gummy liquid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:16]2=[N:17][CH:18]=[C:19]3[CH:23]=[N:22][N:21]([CH3:24])[C:20]3=[C:15]2[CH:14]=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[C:6]([C:13]2[N:25]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]3=[N:17][CH:18]=[C:19]4[CH:23]=[N:22][N:21]([CH3:24])[C:20]4=[C:15]3[CH:14]=2)=[CH:7]1
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3c4c(cnc32)cnn4C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A solution of 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.22 g, 0.46 mmol, [WO2009/152133, Example #42]) in DCM (10 mL) was cooled to about 0° C. BBr3 (1.0 M in DCM, 1.39 mL, 1.39 mmol) was added dropwise. The mixture was stirred at rt for about 16 h. The mixture was cooled to about 0° C. and MeOH (0.5 mL) was added dropwise followed by a solution of saturated aqueous NaHCO3 (6 mL). The mixture was concentrated in vacuo and the residue was partitioned between EtOAc (2×75 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was isolated and washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (12 g silica gel column, EtOAc/MeOH/Et3N 100:10:0 to 100:10:1) to give 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-ol (0.21 g, 99%): LC/MS (Table 2, Method a) Rt=2.10 min; MS m/z 472 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][C:2]=1/[C:12](/[CH3:25])=[CH:13]/[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C.O>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][C:2]=1/[C:12](/[CH3:25])=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)CCCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)CCCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.8 %

Procedure:
300 mg of ethyl p-[(E)-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten -2-yl)propenyl]benzoate are treated in 20 ml of ethanol with 2 ml of 2.5M sodium hydroxide solution. The mixture is stirred at room temperature for 48 hours, diluted with water and extracted with diethyl ether. The aqueous phase is acidified, extracted with ether. The ethereal phase is washed with water, dried and evaporated. There are obtained 200 mg of p-[(E)-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)propenyl]benzoic acid of m.p. 198°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10](O)[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:30]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10]([Cl:30])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(Cl)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of [benzhydryl-(2-hydroxybutyl)amino]acetic acid tert-butyl ester (7.4 g, 20 mmol, 1 eq.) in dry CHCl3 (50 mL) at 0° C. was added SOCl2 (3.13 mL, 43 mmol, 2.15 eq.) dropwise. After 30 min, the solvent was removed in vacuo to afford [benzhydryl-(2-chlorobutyl)amino]acetic acid tert-butyl ester (99% crude yield), which was used without further purification. ESMS: 388.3 [M+H].