Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH3:31])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1)(=[O:23])=[O:22]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([N:20]([CH3:31])[CH3:19])(=[O:22])=[O:23])[CH:29]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CN(C)S(=O)(=O)c1cccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N,N-dimethyl 3-bromobenzenesulfonamide (Combiblocks), the title compound was obtained as a yellow oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[S:35])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2c(Cl)cccc2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2c(Cl)cccc2c1=S
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl-8-chloro-1-(4-iodobenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (736 mg, 1.57 mmol) and Lawesson's Reagent (445 mg, 1.10 mmol, 0.7 equiv) were combined in toluene (8 mL) and placed into an oil bath preheated at 105° C. for 15 minutes. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 40:60; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: [H][H]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, 5% Pd/C catalyst (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 5–10 psi of hydrogen pressure for a period of 10–15 h The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100–105 g, 80–83%).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=1[C:22]1[N:27]=[CH:26][C:25]2[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:39])=O)[CH:35]=3)=[N:29][NH:30][C:24]=2[CH:23]=1.CN.C1COCC1.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)C=O>[Cl:21][C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([O:17][CH3:18])=[C:11]([Cl:10])[C:12]=1[C:22]1[N:27]=[CH:26][C:25]2[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([NH:4][CH3:1])=[O:39])[CH:35]=3)=[N:29][NH:30][C:24]=2[CH:23]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
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: C1CCOC1
Product: CNC(=O)Cn1cc(-c2n[nH]c3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ncc23)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (9.3 μL, 0.054 mmol) was added to a mixture of {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid (8.0 mg, 0.018 mmol), 2.0 M methylamine in THF (9.8 μL, 0.020 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (8.7 mg, 0.020 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at r.t. for 3 h, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=461.0/463.0.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
24.3 g (100 mmol) of 9-phenylcarbazole was put into a 2 L Meyer flask, and dissolved in 600 mL of glacial acetic acid. Then, 17.8 g (100 mmol) of N-bromosuccinimide was slowly added, and the solution was stirred for about 12 hours at room temperature. This solution was dropped into 1 L of ice water while stirring. A white solid precipitated was collected by suction filtration, and then washed with water three times. This solid was dissolved in 150 mL of diethyl ether, and the solution was washed with a saturated aqueous solution of sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated, and then the residue was dissolved in ca. 50 mL of ethanol. The precipitate formed as a white solid was collected by suction filtration and dried, giving 28.4 g (88% yield) of 3-bromo-9-phenylcarbazole as white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9](O)=O.S(Cl)(Cl)=[O:13]>>[O:13]=[C:8]1[CH2:9][C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7]1
Reactant: O=C(O)CCCc1cccs1
Reactant: O=S(Cl)Cl
Product: O=C1CCc2sccc2C1

Procedure:
4-(2-Thienyl)butyric acid was reacted with thionyl chloride and stannic chloride to provide 5-oxo-4,5,6,7-tetrahydrobenzothiophene, which upon reaction with hydrazine and sodium hyroxide gave 4,5,6,7-tetrahydrobenzothiophene. A solution of 13.3 g of 4,5,6,7-tetrahydrobenzothiophene in 150 ml of dichloromethane was added dropwise to a stirred suspension of 13.1 g of ethyl oxalyl chloride and 14.0 g of aluminum chloride in 200 ml of dichloromethane. The reaction mixture was stirred for twelve hours at 25° C. following the addition. The reaction mixture was poured into 500 g of ice and then the organic layer was separated, dried, and the solvent was removed by evaporation to give 19.2 g of ethyl α-oxo-α-(4,5,6,7-tetrahydro-2-benzothienyl)acetate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[OH-].[Na+].OS(O)(=O)=O>C1(C)C=CC=CC=1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 N H2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:9]([NH2:10])=[C:8]([NH2:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1.[CH:14](O)=O>>[CH:1]1([N:4]2[C:9]3[N:10]=[CH:14][NH:11][C:8]=3[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1
Reactant: Nc1c(N)n(C2CC2)c(=O)[nH]c1=O
Reactant: O=CO
Product: O=c1[nH]c(=O)n(C2CC2)c2nc[nH]c12

Procedure:
A solution of 12 g of 1-cyclopropyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (IV) in 50 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 11.2 g (V). The amide (V) was refluxed in 40 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off. Yield 7 g (60%) (VI) NMR (see Table I).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:18][NH2:19])[CH2:12][CH3:13]>C(O)C>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH2:11][CH2:12][CH3:13])[CH:16]=1
Reactant: CCCOc1cc(CN)ccc1OC
Reactant: O=c1[nH]nc(Cl)c(Cl)c1Cl
Solvent: CCO
Product: CCCOc1cc(CNc2c(Cl)n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 2 h

Procedure:
A mixture comprising 997 mg of 4,5,6-trichloro-3(2H)pyridazinone, 3.20 g of 3-n-propoxy-4-methoxybenzylamine and 30 ml of ethanol, was refluxed under stirring for 2 hours. Ethanol was distilled off under reduced pressure, and dilute hydrochloric acid was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light brown viscous oily substance. The residue was subjected to silica gel column chromatography, and the second fraction obtained by eluting with a solvent mixture of benzene-ethyl acetate (2.5:1 v/v) was separated to obtain a colorless solid substance. The product was crystallized from a solvent solution of methanol-diethyl ether, to obtain 513 mg of the above identified compound having a melting point of from 181° to 183° C. as colorless crystals.
Reaction SMILES: C(OP(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(OCC)=O)C.Cl[CH2:23][C:24]1[CH2:31][S:30][CH:29]2[N:26]([C:27](=[O:53])[CH:28]2[NH:32][C:33](=[O:52])[C:34]([C:38]2[N:39]=[C:40]([NH:43][P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[S:41][CH:42]=2)=[N:35][O:36][CH3:37])[C:25]=1[C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)=[O:55].[SH:66][C:67]1[S:71][N:70]=[N:69][CH:68]=1.[Na].O>CC(C)=O>[CH3:65][O:64][C:61]1[CH:60]=[CH:59][C:58]([CH2:57][O:56][C:54]([C:25]2[N:26]3[CH:29]([S:30][CH2:31][C:24]=2[CH2:23][S:66][C:67]2[S:71][N:70]=[N:69][CH:68]=2)[CH:28]([NH:32][C:33](=[O:52])[C:34]([C:38]2[N:39]=[C:40]([NH:43][P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[S:41][CH:42]=2)=[N:35][O:36][CH3:37])[C:27]3=[O:53])=[O:55])=[CH:63][CH:62]=1
Reactant: Sc1cnns1
Reactant: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CCl)CSC23)cs1)OCC
Agent: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CSc4cnns4)CSC23)cs1)OCC
Yield: 76.8 %

Procedure:
[6R-[6-α, 7-β (Z)]]-3-(chloromethyl)-7-[[[2-[(diethoxyphosphinyl)amino]-4-thiazolyl]-(methoxy-imino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (4-methoxyphenyl)methyl ester (0.8 g) and 0.4 g sodium 5-mercapto-1,2,3-thiadiazole were stirred in 30 ml acetone plus 15 ml water for 30 minutes. The solvent was evaporated to dryness and the residue was columned on Biosil A using methylene chloride containing 0.5 to 1.0% methanol to give 687 mg of product; MS ((+)FAB) 770 (M+H); IR (KBr,cm-1) 1786, 1720.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.Cl[C:22]1[C:23]([F:32])=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:22]3[CH:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=3[F:32])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c([N+](=O)[O-])cc3F)CC2)CC1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
2d (0.12 g), 5-chloro-4-fluoro-2-nitro-phenylamine (0.1 g) and diisopropylethylamine (0.1 mL) were combined in 1.2 mL of DMSO and stirred at 110° C. for 3 days. The mixture was cooled to room temperature, diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum and purified on column chromatography (eluent: 10 to 50% EtOAc in hexane+0.1% triethylamine) to yield 60a.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:13][C:14]1[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=1.Cl[C:22](OC(Cl)(Cl)Cl)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:22](=[O:23])[N:13]([C:14]4[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nn(C)cc1Nc1c(N)cnc2ccc(Br)cc12
Solvent: ClCCl
Product: Cc1nn(C)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6-bromo-N*4*-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-3,4-diamine (Stage A.2, 3.15 g, 8.15 mmol) and TEA (1.36 ml, 9.79 mmol) in DCM (65 ml) was added under argon, after cooling with an ice-bath, a solution of trichloromethyl chloroformate (1.08 ml, 8.97 mmol in DCM (65 ml). The mixture was stirred for 25 min at 0° C. Then the RM was quenched with sat. aqueous NaHCO3 (300 ml) and 10 M aqueous NaOH (4 ml) and well stirred. The phases were separated and extracted with EtOAc (3×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a brownish solid (HPLC tR 2.29 min (Method A); M+H=360; M−H=358 MS-ES)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([O:25][C@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]3[CH2:49][CH2:50]3)[CH:37]=1)[CH2:33][C:32]1[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=1[Cl:26])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O)c1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)S(C)(=O)=O
Yield: 68 %

Procedure:
To a solution of 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (120 mg, 0.326 mmol) in DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (137 mg, 0.326 mmol), EDC (187 mg, 0.977 mmol) and DMAP (19.90 mg, 0.163 mmol) were added, and the mixture was reacted at room temperature for 6 hours. The mixture was portioned between DCM and 1N HCl (50 ml) and the desired compound was extracted with DCM (3×50 ml). Crude (S)-4-(2-(2-(5-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained and used in the next step without any additional purification (170 mg, 0.221 mmol, 68% yield). MS/ESI+ 770.1 [MH]+.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COc1cccc(B(O)O)c1
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: COCCOC
Product: COc1cccc(-c2ccc(N)c(C(=O)O)c2)c1
Temperature: 80 °C

Procedure:
To a solution of 5-iodo-2-aminobenzoic acid (2.6g; 10 mmol) in ethylene glycol dimethyl ether (DME, 20 mL) add tetrakis(triphenylphosphine)palladium(0) (150 mg) under argon. After the catalyst dissolved completely, add successively 3-methoxybenzeneboronic acid (1.65 g; 11 mmol) and sodium carbonate (1M in water, 30 mL). Heat the mixture at 80° C. for 1 hour. Cool the reaction mixture then wash with 50% EtOAc in hexane. Filter the aqueous layer through a short pad of celite to remove palladium black and carefully pour the filtrate into cold 3N hydrochloric acid (25 mL) under stirring. Collect the precipitate by filtration and air-dry to obtain 5-(3-methoxyphenyl)-2-aminobenzoic acid as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[N:22]([CH3:23])[CH:21]=[C:8]2[C:9]3[CH:19]=[C:18]([F:20])[CH:17]=[C:11]4[CH:12]=[CH:13][C:14](=[N:15][NH:16][C:7]2=[C:6]1[C:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=1)[C:10]=34)[CH3:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH2:3]([CH:5]1[N:22]([CH3:23])[CH:21]=[C:8]2[C:9]3[CH:19]=[C:18]([F:20])[CH:17]=[C:11]4[CH:12]=[CH:13][C:14](=[N:15][NH:16][C:7]2=[C:6]1[C:24]1[CH2:25][CH2:26][N:27]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:28][CH:29]=1)[C:10]=34)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1C(C2=CCNCC2)=C2NN=C3C=Cc4cc(F)cc(c43)C2=CN1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C(C2=CCN(S(C)(=O)=O)CC2)=C2NN=C3C=Cc4cc(F)cc(c43)C2=CN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Example 9 (35 mg, 0.08 mmol) in dichloromethane (5 mL) was added triethylamine (0.07 mL, 0.482 mmol) and methanesulfonyl chloride (14 mg, 0.121 mmol). The mixture was stirred at room temperature for 2 hours, and purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, CD3OD): δ 0.81-0.86 (m, 3H), 1.22-1.30 (m, 1H), 1.37-1.45 (m, 1H), 2.62-2.69 (m, 1H), 2.73-2.81 (m, 1H), 2.88 (s, 3H), 2.98 (s, 3H), 3.36-3.41 (m, 1H), 3.42-3.48 (m, 1H), 3.96 (dd, J=5.80, 3.05 Hz, 2H), 4.28 (dd, J=9.00, 5.65 Hz, 1H), 6.11 (s, 1H), 7.21-7.29 (m, 2H), 7.35 (d, J=5.49 Hz, 1H), 7.77 (dd, J=10.68, 2.75 Hz, 1H), 8.22 (d, J=5.19 Hz, 1H), 11.51 (s, 1H). MS (ESI+) m/z 441 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (3.0 g, 8.5 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.2 g, 10.0 mmol). The title compound was obtained as a solid (3.3 g, 73% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.66 (1H, m), 8.47 (1H, m), 3.87 (3H, m), 2.82 (2H, m), 1.73 (2H, m), 1.37 (9H, s), 1.31 (2H, m).
Reaction SMILES: [Na].[CH2:2](O)C.[CH:5]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.CI>O>[CH:15]1[C:16]2[CH:17]([C:19]([O:21][CH3:2])=[O:20])[C:18]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCO
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: [Na]
Solvent: O
Solvent: CI
Product: COC(=O)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sodium ethoxide solution is prepared from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the suspension obtained is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and combined with 126.73 mL (2.0 mol) of methyl iodide with stirring. The solution formed is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 69d) (308 mg, 0.62 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added butyrylchloride (90 μL, 0.87 mmol) at room temperature. The resultant solution stirred for 90 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (35 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (352 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.42 (s 1H), 7.93 (dm, 0.7=8.8 Hz, 2H), 7.85 (dm, J=8.8 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 6.94 (d, 8.6 Hz, 1H), 5.74 (d, J=9.2 Hz, 1H), 5.03 (dd, J=6.5, 9.0 Hz, 1H), 4.66 (pentet, 6.3 Hz, 1H), 2.38 (t, J=7.2 Hz, 2H), 2.35 (s, 1.70 (sextet, J=7.4 Hz, 2H), 1.44 (d, J=6.1 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 0.81 (s, 9H), 009 (s, 3H), −0.01 (s, 3H).