Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:22][CH2:23]3)=[CH:14][N:13]=2)[C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1)(=[O:30])[CH3:29]
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2ncnn2c1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c3ncnn3c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 140 °C
Yield: 56.9 %

Procedure:
A sealed tube was charged with 6-chloro-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)[1,2,4]triazolo[1,5-a]pyridin-8-amine 108d (196 mg, 0.51 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 114e (200 mg, 0.52 mmol), PdCl2(dppf) (24 mg, 0.030 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (83 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.2 mL). The mixture was heated at 140° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 122a (200 mg, 56%) as a white solid. MS-ESI: [M+H]+ 689.3.
Reaction SMILES: ClC[O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10].Br>>[OH:15][C:5]1[C:4]([OH:3])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: O=Cc1cc(OCCl)c(O)cc1[N+](=O)[O-]
Agent: Br
Product: O=Cc1cc(O)c(O)cc1[N+](=O)[O-]
Yield: 92.4 %

Procedure:
5-Chloromethoxy-4-hydroxy-2-nitrobenzaldehyde (10) (3 g; 0.013 mol) is stirred at 23° C. with 15 ml 48% HBr for two days. The precipitate is removed by filtration, and washed well with H2O, giving 2.2 g (93%) of 4,5-dihydroxy-2-nitrobenzaldehyde (1). The remainder of the product is isolated by ether extraction of the filtrate. Drying the combined ether extracts over Na2SO4, filtering, and removing the ether at reduced pressure, gives the remaining 0.17 g (7%) of (1): mp 201°-203° C.; mass spectrum, m/e 183 (M+); 1HNMR (d6 -Me2CO) δ10.59 (br s,2H), δ10.2(s,1H), δ7.6(s,1H), δ7.3(s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:14][C:4]1[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCc1c(N)cc(Cl)cc1C(=O)OC
Temperature: 70 °C
Yield: 44.7 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-nitrobenzoate (6.18 g, 25.36 mmol) in Methanol (250 ml) at room temperature was added ammonium chloride (13.31 g, 253.65 mmol) followed by deionized Water (125 ml). The mixture was heated to 70° C. in air before the addition of iron (8.5 g, 152.19 mmol). The reaction turned to a dark color over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (250 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3 (aq) (2×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 75:25 Heptane:EtOAc) to give 2.42 g (22%, 7% corrected yields) of methyl 3-amino-5-chloro-2-ethylbenzoate as a yellow oil. The product contains ˜25% ethyl ester and possible ˜15% 4-nitro products. The material was taken through the next step without further purification. LC-MS 31%, 2.00 min (3 minute LC-MS method), m/z=295.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.17 (d, J=2.1 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.87 (s, 3H), 3.86-3.81 (m, 2H), 2.74 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:30])([CH3:29])[C@@H:11]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6].[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:30])([CH3:29])[C@@H:11]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6])=[N+:32]=[N-:33]
Reactant: CN(C)C(=O)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)C(=O)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]
Yield: 90.9 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, (N,N-dimethylcarbamoyl)methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (36c) (200 mg, 0.43 mmol) dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 130 mg (2.0 mmol) of sodium azide (NaN3). After work-up, the crude material (36d) 184 mg (91% yield) was obtained as a colorless viscous oil that was used in the next step without further purification. MS (ESI) m/z 471.2 (M+H)+, 493.1 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:19])([F:18])[CH2:14][CH2:15][CH2:16]O>>[F:12][C:13]([F:19])([F:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCC(F)(F)F
Product: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 66.6 %

Procedure:
A reaction similar to that described in Example 1 (1a) was conducted using methyl 4-hydroxybenzoate (1.19 g) and 4,4,4-trifluorobutan-1-ol (1.00 g) to give 1.29 g of the title compound (white powder).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[C:6]([CH2:14][CH3:15])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[OH2:16].ClCCl>CCC(O)CC.CN(C=O)C>[CH2:14]([C:6]1[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=[C:4]([O:16][CH:6]([CH2:14][CH3:15])[CH2:5][CH3:4])[CH:5]=1)[CH3:15]
Reactant: O
Reactant: CCc1cc(Cl)nn2c(N)nnc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCC(O)CC
Product: CCc1cc(OC(CC)CC)nn2c(N)nnc12
Reaction time: 8 h

Procedure:
3-Pentanol (1.2 ml) was initially charged at RT with stirring. Thereafter, sodium hydride (77 mg) was added while cooling with ice. After stirring at 55° C. for 2.5 h, 6-chloro-8-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.003, 60 mg), dissolved in 3-pentanol (1.5 ml) and 4 ml of DMF (4 ml), was added dropwise. After stirring for 2 h, the reaction mixture was left to stand at RT overnight, admixed with water and dichloromethane and then extracted three times more with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 70 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:11][C:12](=[O:13])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: CCN(CC)C(=O)CCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 50.7 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at ca. 55° C. with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO3 (0.69 g, 3.60 mmol) to afford 0.37 g (51% yield) of the title compound (1) after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56° C. 1H NMR (CDCl3, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J=7.2 Hz, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20]CC)=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+:28].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:31][C:30]([C:29]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([O-:20])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:28]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C([O-])c2cc3cc(OCc4ccccc4)ccc3n2C1
Temperature: 34 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a 5000 mL, 3-neck round bottom flask equipped with a mechanical stirrer, a temperature probe, a nitrogen inlet, and a heating mantle was added ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (150 g, 508 mmol) followed by anhydrous THF (2000 mL). To the resulting mixture was added potassium t-butoxide (1.0 M in THF, 762 mL, 762 mmol) via an addition funnel over 15 min (temperature increased from 20° C. to 26° C. over the addition time). The mixture was stirred for 1 h and ethyl acrylate (166 mL, 1.52 mol) was added via addition funnel over 15 min (temp increase to 34° C.). The addition funnel was replaced with a reflux condenser and the mixture heated to reflux and stirred for 18 h (the product started to appear as a white precipitate after only 0.5 h of heating). The flask was cooled to room temperature. The resulting precipitate was collected by vacuum filtration. The filtrate was concentrated to approximately 750 mL and diluted with MTBE (approx. 500 mL). Additional product precipitated and this material was filtered and added to the original filter cake. The combined solids were washed with cold THF:MTBE (1:1) and vacuum oven dried (45° C., 2 Ton) to give potassium 7-(benzyloxy)-2-(ethoxycarbonyl)-3H-pyrrolo[1,2-a]indol-1-olate as an off-white solid (120 g, 61% yield). Exact mass calculated for C21H19NO4 (protonated keto-enol form): 349.1, found: LCMS m/z=350.3, [M+H+]; 1H NMR (400 MHz, d6-DMSO) δ ppm 1.18 (t, J=7.1 Hz, 3 H), 3.99 (q, J=7.1 Hz, 2 H), 4.59 (s, 2 H), 5.09 (s, 2 H), 6.14 (s, 1 H), 6.80 (dd, J1=8.8, J2=2.3 Hz, 1 H), 7.11 (d, J=2.3 Hz, 1 H), 7.30 (m, 2 H), 7.38 (m, 2 H), 7.46 (m, 2 H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20])=O)(C)(C)C>Cl.CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (500 mg), as described in Example 3 Step A, in 10 mL of 4 N HCl/MeOH was stirred at room temperature for 1 h. Then the solvent was removed. The residue was dissolved in EA (30 mL) and pH value was adjusted to 9˜10 with saturated aq. NaHCO3. The organic layers was washed with water (10 mL), brine, dried over sodium sulfate and concentrated to give the title product as a pale brown solid. LC/MS m/z=343.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[S:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:23])=[O:2])=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(-c2ncc(-c3ccc(OC)cc3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
A solution of 1.4 g (4.3 mmol) 3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid methyl ester from Preparation 10 in a 3:1:1 mixture of THF/methanol/water was added 10 mL (10 mmol) 1N NaOH. The mixture was stirred 14 hours at room temperature before concentrating on a rotary evaporator. The residue was treated with 6M HCl then filtered, washed with water (1×) and dried in a vacuum oven overnight at 70° C. to provide 1.2 g (88%) of desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.[Li]CCCC.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[C:19]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
To a solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (Aldrich Chemicals, 1.77 g, 10 mmol) in THF (100 mL) at −78° C. was added nBuLi (6.6 mL, 1.6 M in Hexane, 10.6 mmol) dropwise. After 10 minutes, hexanoyl chloride (1.68 mL, 12 mmol) was added. After 30 minutes the solution was allowed to warm to rt, at which time the reaction was quenched with saturated ammonium chloride solution. After 10 minutes, 1 M NaOH was added, and the mixture extracted 3 times with ethyl acetate. The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (0% to 20% EtOAc/Hexane gradient) afforded pure product (1.98 g, 72%). 1H NMR (500 MHz, CDCl3) δ ppm 0.96-0.81 (m, 6H) 1.40-1.26 (m, 4H) 1.74-1.59 (m, 2H) 3.04-2.81 (m, 2H) 4.75 (dt, J=13.8, 6.7 Hz, 1H) 5.64 (d, J=7.32 Hz, 1H) 7.44-7.23 (m, 5H).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[NH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([OH:30])=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]=1[F:33].O.[C:35]([O:38][CH2:39][CH3:40])(=O)C>>[NH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:40][C@H:39]4[CH2:35][O:38]4)=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]=1[F:33]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OC[C@H]1CO1
Temperature: 50 °C

Procedure:
After adding dimethylformamide (8 ml), p-toluenesulfonic acid (2R)-glycidyl ester (1000 mg) and potassium carbonate (940 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (1000 mg), the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (659 mg) as light yellow crystals.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]([S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
3 M NaOH (5 mL, 15 mmol) was added to a solution of 5-(benzyloxy)-6-methoxy-indole (1.0 g, 3.9 mmol), tetrabutylammonium hydrogen sulfate (0.400 g, 1.18 mmol) and benzenesulfonyl chloride (1.04 g, 5.92 mmol) in DCM (25 mL). The mixture was stirred overnight at room temperature and diluted with DCM and water. The organic phase was washed with water (1×), dried (MgSO4) and evaporated. The crude product was purified through a plug of silica gel using DCM as the eluent to give the title compound (1.1 g) as a white solid. MS m/z 394 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CN(C)C=O.O>[CH2:16]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:17]=[CH2:18]
Reactant: COc1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1OC
Reaction time: 0.5 h
Yield: 79 %

Procedure:
124 g of 2-methoxyphenol and 152 g of potassium carbonate in 500 ml of dimethylformamide are brought to 60° C. with stirring for 30 minutes. 127 g of allyl bromide are introduced and the reaction medium is then left at 60° C. for 1 hour. It is diluted with 2 l of water and extracted with ethyl ether and the organic phase is washed with sodium hydroxide. The organic phase is dried and the ether evaporated off. The product is then distilled at 115° C. and at 20 mmHg to obtain 129.6 g of the expected compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=3[F:24])[C:10]=2[N+:25]([O-])=O)=[CH:4][C:3]=1[NH:28][S:29](=[O:32])(=[O:31])[NH2:30].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:25][C:10]1[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:28][S:29](=[O:31])(=[O:32])[NH2:30])[CH:4]=1
Reactant: NS(=O)(=O)Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])ccc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1ccc(F)c(NS(N)(=O)=O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
597 mg crude N-(2-fluoro-5-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}phenyl)sulfuric diamide (1.028 mmol, 1 eq.) were dissolved in 20 mL THF, warmed to 50° C., treated with a solution of 3.044 g sodium dithionite (17.484 mmol, 17 eq.) in 16 ml of water dropwise over a period of 30 minutes. The resulting mixture was stirred at this temperature for another 5 h. Upon cooling to rt the phases separated. The organic layer was separated, concentrated in vacuo and redissolved in ethyl acetate. The aqueouse layer was diluted with saturated sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic layers were washed once with half saturated brine and once with brine saturated, dried, filtered and concentrated in vacuo, providing 547 mg of crude product which was used in the subsequent transformations without further purification.
Reaction SMILES: [CH:1](N(CC)C(C)C)([CH3:3])[CH3:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:19][CH:18]2[NH:20][C:21]2[C:22]3[N:36]=[N:35][N:34]([CH:37]4[CH2:41][CH:40]([CH2:42][OH:43])[CH:39]([OH:44])[CH:38]4[OH:45])[C:23]=3[N:24]=[C:25]([S:27][CH2:28][CH2:29][C:30](F)(F)F)[N:26]=2)=[CH:13][CH:12]=1>ClCCl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:19][CH:18]2[NH:20][C:21]2[C:22]3[N:36]=[N:35][N:34]([CH:37]4[CH:38]5[O:45][C:1]([CH3:3])([CH3:2])[O:44][CH:39]5[CH:40]([CH2:42][OH:43])[CH2:41]4)[C:23]=3[N:24]=[C:25]([S:27][CH2:28][CH2:29][CH3:30])[N:26]=2)=[CH:15][CH:16]=1
Reactant: OCC1CC(n2nnc3c(NC4CC4c4ccc(F)cc4)nc(SCCC(F)(F)F)nc32)C(O)C1O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCSc1nc(NC2CC2c2ccc(F)cc2)c2nnn(C3CC(CO)C4OC(C)(C)OC43)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (1.29 g) was added to a solution of [3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084) (1.0 g) and the product of step d) (0.75 g) in dichloromethane (25 ml). The reaction mixture was stirred at room temperature for 3 hours, then washed with water, dried and evaporated. The residue was purified (SiO2, ethyl acetate:isohexane 1:1 as eluent) to afford the subtitle compound (1.25 g).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].IC.[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:23])[C:19]=3[NH:20]2)=[CH:12][CH:11]=1>CN(C=O)C.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:23])[C:19]=3[N:20]2[CH3:1])=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2c1[nH]c1cc(Br)ccc21
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c2c(c3ccc(Br)cc31)CCCC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Cs2CO3 (2.5 g, 7.5 mmol) and iodomethane (0.47 mL, 7.5 mmol) were added to a solution of 7-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.7 g, 6.3 mmol) in DMF (21 mL), and the resulting mixture was stirred for 4 h at ambient temperature. The reaction was diluted with H2O (25 mL), and the resulting solution was stirred for 15 minutes. The resulting precipitate was collected by filtration, washed with H2O (200 mL) and dried to yield the title compound (1.5 g, 87%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=1.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.25 (dd, J=8.5, 1.5 Hz, 1H), 3.98 (s, 3H), 2.96 (t, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 2.13-2.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].O.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)O
Yield: 93 %

Procedure:
To a solution of ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate (1.49 g, 4.49 mmol) in tetrahydrofuran (30 mL), methanol (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.38 g, 9.00 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 14 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was filtered and dried to afford the title compound in 93% yield (1.27 g): mp 286-289° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.88-7.34 (m, 5H), 4.10-3.76 (m, 4H), 2.49 (s, 3H); MS (ES+) m/z 304.3 (M+1).