Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].Cl[Si](C)(C)C.[CH2:12]([O:19][C:20]([NH:22][C@H:23]([C:35](O)=[O:36])[CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25]([OH:27])=[O:26])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[SiH3]OC(=O)[C@@H](C)N.Cl>CN(C)C=O.O1CCCC1.C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]([NH:22][C@H:23]([C:35]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:36])[CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](=[O:26])[OH:27])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: C[C@@H](N)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[C@@H](N)C(=O)O[SiH3]
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 78.2 %

Procedure:
D-Alanine (20 g, 0.225 mole) was dissolved in dimethylformamide (400 ml), treated with chlorotrimethylsilane (26.8 g, 0.250 mole) and the mixture stirred at room temperature until a homogeneous solution was obtained (approx. 45 minutes). Meanwhile, Nα -benzyloxycarbonyl-β-benzyl-L-aspartic acid (72 g, 0.200 mole) was dissolved in a 1:1 mixture of dimethylformamide and tetrahydrofuran (880 ml), cooled to a -15° C. and treated with N-methylmorpholine (22.4 ml, 0.200 mole) and isobutyl chloroformate (26.2 ml, 0.200 mole). After 8 minutes' activation at -15° C. the precooled solution of D-alanine silyl ester from above was added, followed by the dropwise addition of N-methylmorpholine (22.4 ml, 0.200 mole), ensuring that the temperature of the reaction mixture was maintained at -15° C. The solution was allowed to warm to room temperature slowly and stirred for several hours before acidifying to pH 1-2 (with cooling) using aqueous hydrochloric acid. Chloroform was added, the phases separated and the aqueous layer re-extracted with chloroform. The combined organic extracts were washed with 1N hydrochloric acid (3×), saturated aqueous sodium chloride and dried (MgSO4). After evaporation of the solvent under reduced pressure, the oily residue was triturated with ether. The resulting solid was filtered and dried in vacuo to give Nα -benzyloxycarbonyl-β-benzyl-L-aspartyl-D-alanine (67 g), m.p. 158°-159° C., which was homogeneous by TLC.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)[CH2:15][C:14]2=[O:30])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[C:31](#[N:33])[CH3:32]>O1CCOCC1>[NH2:7][C:6]1[C:5]2[C:4](=[CH:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][C:20]4[NH:24][C:23]5[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:22]=5[N:21]=4)[CH2:15][C:14]3=[O:30])=[CH:9][CH:8]=2)[N:3]=[C:31]([CH3:32])[N:33]=1
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1N
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)c2ccc(CN3CCC(Cc4nc5ccc(Cl)cc5[nH]4)CC3=O)cc2n1
Temperature: 0 °C
Yield: 17.8 %

Procedure:
A stream of hydrogen chloride gas is bubbled intermittently through an ice-cold mixture of 2-amino-4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile hydrochloric acid salt (57 mg, 0.123 mmol), EXAMPLE 814, Part E, and acetonitrile (0.03 mL, 0.93 mmol) in 1.5 mL of dioxane for six hours. The dioxane is removed; the residue is purified by reverse phase HPLC (0-40% ACN/H2O). The desired product (9.5 mg, 12% yield) is isolated as a clear wax. C23H23ClN6O MS m/z: 435, 437.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.Cl>[OH-].[Na+]>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:11])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Reaction time: 2 h
Yield: 56.4 %

Procedure:
In 20 ml of IN sodium hydroxide solution, 3.28 g of phenylalanyltyrosine was dissolved and the solution was cooled with ice. To the cold solution were added dropwise 1.7 g of 4-methoxybenzoylchloride and 10 ml of IN sodium hydroxide solution. After stirring for two hours, the mixture was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 2.6 g of N-(4-methoxybenzoyl)-phenylalanyltyrosine in a yield of 56%.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:31])=[CH:5][CH:6]=4)[CH:14]=3)=[C:19]([C:20]([F:23])([F:21])[F:22])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 87 %

Procedure:
As described for Example 32, 4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (100 mg, 0.23 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (100 mg, 87%) which was obtained as a white solid. MS: m/e=498.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[O:12][CH3:13].Br[C:15]1[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[C:4]([F:11])[C:3]=1[O:12][CH3:13]
Reactant: Nc1cnc(Br)cn1
Reactant: COc1c(Br)ccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Temperature: 80 °C

Procedure:
A mixture of (4-bromo-2-fluoro-3-methoxyphenyl)boronic acid (940 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (1.31 g, 7.56 mmol) was treated with EtOH (12.4 ml), toluene (12.8 ml), and aqueous Na2CO3 (2.0 N, 9.44 ml, 18.9 mmol), and the resulting mixture deoxygenated by sparging with for 10 minutes. Pd(PPh3)4 (218 mg, 0.189 mmol) was then added, and the mixture heated at 80° Celsius for 17 h. The reaction was cooled to rt and then partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was isolated, dried over MgSO4, and concentrated to dryness. The resultant residue was suspended in DCM and the title compound isolated by filtration (300 mg, 27%), which was used without further purification. Additional product was obtained by concentrating the filtrate to dryness and subjecting the residue to FCC (560 mg, 50%). MS (ESI): mass calcd. for C11HgBrFN3O, 296.99; m/z found, 298.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.00 (d, J=1.5, 1H), 7.54-7.49 (m, 2H), 6.78 (s, 2H), 3.90 (d, J=0.6, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=O)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=[CH2:1])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 1 A solution of potassium tert-butoxide (3.40 g, 30.3 mmol) in THF (249 mL) at 0° C. was treated with methyltriphenylphosphonium bromide (8.79 g, 24.60 mmol), forming a bright yellow suspension. After 1 h, 4-bromo-7-formyl-9H-carbazole-1-carboxamide (prepared according to the procedure of Step 1 of Example 41-1, 4 g, 9.46 mmol) was added, and the resulting suspension was warmed to rt and stirred for 3 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 70:30 hexane-EtOAc to EtOAc). The crude material was suspended in methanol, and the precipitate was collected by filtration and dried. The filtrate was concentrated to provide additional solid which was collected by filtration, dried and combined with the first crop to provide 4-bromo-7-vinyl-9H-carbazole-1-carboxamide as a light brown solid (1.66 g, ca. 90% purity, 50%). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (1 H, s), 8.52 (1 H, d, J=8.3 Hz), 8.06-8.29 (1 H, m), 7.79-7.88 (2 H, m), 7.58 (1 H, br. s.), 7.35-7.45 (2 H, m), 6.78-6.98 (1 H, m), 5.88 (1 H, d, J=17.6 Hz), 5.32 (1 H, d). Mass spectrum m/z 344, 346 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:25]([O:35]N1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>C(Cl)(Cl)Cl>[CH2:28]([O:27][C:25](=[O:35])[N:11]([CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])[CH3:12])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCC(C)(C)CNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN(CC(C)(C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (2,2-Dimethyl-3-methylamino-propyl)-carbamic acid tert-butyl ester (compound PP) (1.05 g, 4.85 mmol) in CHCl3 (10 mL) at ambient temperature was added DIEA (0.84 mL, 4.85 mmol) followed by Cbz-OSu (1.21 g. 4.85 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture then was diluted with CHCl3 (100 mL), and washed with water (2×50 mL) and brine (50 mL). The organic layer was separated and dried over Na2SO4. The removal of the solvents in vacuo yielded crude compound QQ in quantitative yield (1.78 g, 4.85 mmol) as a foamy solid. LC-MS [M+H] 351.6 (C19H30N2O4+H, calc: 351.2). Compound QQ was used directly in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:9][C:10]([C:12]1[N:13]=[C:14]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:18]=[CH:17][CH:16]=2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.CO>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:20]=2[CH:21]=[C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:39])=[O:2])=[O:11])[N:13]=[C:14]3[CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:24][CH:25]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H](NC(=O)c1cc2c(Oc3ccc(C(C)(C)C)cc3)cccc2c(CC2CCCC2)n1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(Oc2cccc3c(CC4CCCC4)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)cc23)cc1
Yield: 89.3 %

Procedure:
A solution of (2S)-{[5-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3,3-dimethyl-butyric acid methyl ester (28 mg, 0.052 mmol) in THF-MeOH (2.0 mL) was treated with LiOH solution (2.0M, 0.400 mL) by the general procedure I to give 24 mg of (2S)-{[5-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3,3-dimethyl-butyric acid as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:13]([SH:24])=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.II>>[N:1]1([CH2:7][CH2:8][N:9]2[C:10](=[O:11])[C:12]3[C:13](=[N:14][C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:16][CH:17]=3)[S:24]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(NCCN1CCOCC1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1CCN1CCOCC1
Yield: 60.8 %

Procedure:
Using the procedure of Example 20, 2.0 g (5.81 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide were treated with 1.47 g (5.81 mmol) of iodine to give 1.21 g of the title compound after recrystallization from isopropanol, mp 163°-165° C.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1>C1COCC1.[Cl-].[Na+].O.[Br-].[Zn+2].[Br-]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:1]#[CH:2])=[CH:8][CH:7]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#C[Mg]Br
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of zinc bromide (9.0 g, 40 mmol) in anhydrous THF (100 mL) at room temperature under a nitrogen atmosphere was added a solution of ethynyl magnesium bromide (0.5 M in THF, 60 mL, 30 mmol). After 5 minutes 4-bromo-iodobenzene was added (5.64 g, 20 mmol) followed by tetrakis triphenyl phosphine palladium (0) (1.15 g, 1.0 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was poured into brine and extracted with ether (4×100 mL). The ether layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): δ 7.51 (d, J=8.5 Hz, 2H), 7.4 (d, J=8.5 Hz, 1H), 3.16 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O.C(OC)(C)(C)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: COC(C)(C)C
Solvent: CCO
Product: COC(=O)N1CCc2ccc(N)cc2CC1
Yield: 99.9 %

Procedure:
A mixture of the compound from Step 1 (50 g, 200 mmol) and 10% palladium on carbon (2.5 g) in ethanol (800 mL) is hydrogenated with shaking at 20 psi. Methyl t-butyl ether is added and the mixture filtered through celite and concentrated to give 44 g (100%) of the title compound as a white solid, mp 100-104° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:16]([O:18][CH:19]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20]1)=[O:17].[Na+].[Cl-]>N1C=CC=CC=1>[CH2:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[N:12][C:16]([O:18][C@@H:19]1[CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][C@H:24]1[CH:25]([CH3:27])[CH3:26])=[O:17])=[O:11])[CH3:14]
Reactant: CCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCS(=O)(=NC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.47 mmol) of (RS)—S-(4-nitrophenyl)-S-ethyl sulfoximide in 4.40 ml of pyridine is mixed drop by drop at room temperature with 0.46 ml (2.17 mmol) of (+) menthyl chloroformate. The batch is stirred for 4 hours at room temperature and then added to dilute NaCl solution. It is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 161 mg (0.41 mmol, corresponding to 87% of theory) of the product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[NH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([Br:44])[CH:42]=2)[N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:36]=1>ClCCCl>[Br:44][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[N:36]=[C:35]2[NH:34][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(Br)ccc21
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (8.41 g, 39.1 mmol) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 9.66 g, 39.1 mmol) in DCE (50 mL) was allowed to stir at rt for 10 min. To this solution was added a solution of tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate (6.1 g, 19.54 mmol) in DCE (50 mL) in one portion and the resulting mixture was heated at 70° C. overnight. The mixture was partitioned between sat NaHCO3 and EtOAc and the phases were separated. The aqueous layer was extracted (×2) with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on flash chromatography (BIOTAGE® eluting with a gradient of 0 to 100% Ether/Hexanes) to afford the title compound as yellow solid contaminated with quinoline. The material was dissolved in ether and washed several times with HCl (1M). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (4.8 g, 48% yield) as yellow solid. The material was used as is in subsequent steps. 1H NMR (500 MHz, CD3OD) δ 8.19 (app d, J=11.3 Hz, 1H), 8.03 (unresolved dd, J=8.9, 11.0 Hz, 1H), 7.67-7.70 (m, 1H), 4.40-4.44 (m, 1H), 3.57-3.61 (m, 1H), 3.47-3.52 (m, 1H), 2.33-2.42 (m, 1H), 2.01-2.13 (m, 2H), 1.91-1.98 (m, 1H), 1.68 (s, 9H), 1.50, 1.42 (s, 9H, rotamers, 2:1 ratio). LCMS: Anal. Calcd. for C22H29BrN4O5: 508, 510; found: 509, 511 (M+H)+.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Sn+2].FC(F)(F)S([O-])(=O)=O.[C:18]([S:22][CH3:23])(=[S:21])[CH2:19][CH3:20].C(O[C@H:28]1[NH:31][C:30](=[O:32])[C@@H:29]1[C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])(=O)C.C(O)(=O)C(O)=O>ClCCl.C(N(CC)CC)C>[C:39]([Si:36]([CH3:37])([CH3:38])[O:35][C@@H:33]([C@@H:29]1[C@@H:28]([S:21][C:18]([S:22][CH3:23])=[CH:19][CH3:20])[NH:31][C:30]1=[O:32])[CH3:34])([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=S)SC
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(SC)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a suspension of Tin(II) trifluoromethanesulfonate (5.58 g) in dichloromethane (27 ml) cooled to -25° C. were added triethylamine (1.62 g) and methyl dithiopropionate (1.20 g) successively. The mixture was stirred for 2 hours at -20° C. and (3R,4R)-4-acetoxy-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-2-oxoazetidine (2.0 g) was added thereto. After stirring for 2 hours at 0° C., the mixture was poured into 20% aqueous solution of oxalic acid (100 ml) and the precipitates were filtered off. The organic layer of the filtrate was separated, dried, and concentrated under reduced pressure. The residue was purified by silica gel (50 g) column chromatography (20% ethyl acetate-hexane) to afford (3S,4R)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1-methylthio-1-propenyl)thio]-2-oxoazetidine (mixture of E and Z isomers) (1.14 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[S:15]1[C:19]2[CH:20]=[CH:21][C:22](B(O)O)=[CH:23][C:18]=2[N:17]=[CH:16]1.[F-].[K+].CC#N>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2].O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:22]2[CH:21]=[CH:20][C:19]3[S:15][CH:16]=[N:17][C:18]=3[CH:23]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: OB(O)c1ccc2scnc2c1
Reactant: COC(=O)c1nc(Br)c(F)c(N)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3scnc3c2)c(F)c(N)c1Cl
Temperature: 150 °C
Yield: 50.9 %

Procedure:
To a 5 mL microwave vial was added methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate (200 mg, 1.0 mmol), benzo[d]thiazol-5-ylboronic acid (237 mg, 1.35 mmol), potassium fluoride (KF; 122 mg, 2.12 mmol), TPPTS-Na (tris-(3-sulfornatophenyl)-phosphine4-hydrate sodium salt, 67 mg, 0.106 mmol) and Pd(OAc)2 (11 mg, 0.053 mmol). Subsequently, CH3CN (1.0 mL) and H2O (3.0 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave at 150° C. for 5 min, with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to room temperature and diluted with dicloromethane, and washed wth water. The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by triturating with Et2O to yield the title compound as a brown solid (172 mg, 51%).
Reaction SMILES: ClC1C=C(NC(=O)C)C=C(S(C2C=NC=CC=2)(=O)=O)C=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]2[CH:31]=[C:32]([NH:55][C:56](=[O:58])[CH3:57])[CH:33]=[C:34]([C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[CH:38]=[CH:39][N:40]4[Si](C(C)C)(C(C)C)C(C)C)[CH:35]=2)(=[O:29])=[O:28])[CH:22]=1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:34]3[CH:33]=[C:32]([NH:55][C:56](=[O:58])[CH3:57])[CH:31]=[C:30]([S:27]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)(=[O:29])=[O:28])[CH:35]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:39]1
Reactant: CC(=O)Nc1cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)cc(S(=O)(=O)c2cccnc2)c1
Agent: CC(=O)Nc1cc(Cl)cc(S(=O)(=O)c2cccnc2)c1
Product: CC(=O)Nc1cc(-c2cccc3[nH]ccc23)cc(S(=O)(=O)c2cccnc2)c1

Procedure:
N-[3-chloro-5-(pyridine-3-sulfonyl)-phenyl]-acetamide was converted to N-[3-(pyridine-3-sulfonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-acetamide and the triisopropylsilyl protecting group was removed as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 9.17 (br s, 1H), 8.82 (br s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.96 (d, J=1.4 Hz, 1H), 7.63 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.31 (d, J=3.3 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.4 Hz, 1H), 6.53 (d, J=3.2 Hz, 1H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[C:5]([C:34]([O:36]CC1C=CC(OC)=CC=1)=[O:35])=[CH:6][N:7]2[CH2:32][CH3:33].[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[C:5]([C:34]([OH:36])=[O:35])=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a suspension of 4-methoxybenzyl 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (8.4 g, 13.04 mmol) in a mixture of Methanol (90 mL) and Water (30.0 mL) was added KOH (1.463 g, 26.1 mmol) portionwise. The resulting mixture was stirred under reflux for 1.5 h. The mixture was then cooled down to r.t., concentrated, diluted with water (150 mL) and adjusted pH to 2-3 using 6 N HCl (aq.). The precipitates were collected by filtration and dried to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6.7 g, 12.79 mmol, 98% yield) as a white solid. LCMS: (M+H)+: 524.2.