Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
Methyl 2-({4-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.547 g, 1.45 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled to −20° C. Triethylamine (0.22 g, 2.17 mmol) was added dropwise followed by the dropwise addition of methylsulfonyl chloride (0.18 g, 1.59 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature. Excess of triethylamine was removed by addition of diethyl ether (5 ml) and filtering off the precipitate. The organic phase was washed with three portions of brine (10 ml) and dried (MgSO4). The solvent was removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.317 g of methyl 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (yield 48%).
Reaction SMILES: [Cl-].[C:2]1([N:8](C2C=CC=CC=2)C([N+]2C=CC=CC=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46](O)=[O:47])[CH:43]=2)[NH:38][CH:37]=1.C(N(CC)CC)C>O>[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46]([NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:47])[CH:43]=2)[NH:38][CH:37]=1
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
An ice-cold solution of diphenylamino carbonyl pyridinium chloride (3.5 g) in water (35 ml) was added dropwise to a mixture of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (3.5 g), triethylamine (2.8 ml) and ice-water (70 ml) with rapid stirring over 15 min. After stirring the mixture for a further 10 min. it was extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with water (1×50 ml), dried (Na2SO4), and evaporated in vacuo to give an orange solid (3.6 g).
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH2:3]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([Br:1])[C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: O=C1CCCCC1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step AAD (1): Followed the method of B. Miller and H.-S. Wong Tetrahedron 1972, 28, 2369. Bromine (0.082 mL, 1.59 mmol) in was added dropwise over a period of 15 min to a solution of 2-benzylcyclohexanone (300 mg, 1.593 mmol) in chloroform (5 mL). The reaction mixture was stirred at rt for 2 h, then concentrated in vacuo to afford 2-benzyl-6-bromocyclohexanone. The crude product, which is prone to decomposition, was used for subsequent chemistry without purification or characterization.
Reaction SMILES: OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.C(=O)([O-])[O-].[K+].[K+].[C:19]([NH:22][C:23]1[C:24]([I:38])=[C:25]([C:30]([I:37])=[C:31](N=C=O)[C:32]=1[I:33])[C:26]([NH:28][CH3:29])=[O:27])(=[O:21])C.[CH3:39][N:40]([CH3:43])[CH:41]=[O:42]>>[I:37][C:30]1[C:25]([C:26]([NH:28][CH3:29])=[O:27])=[C:24]([I:38])[C:23]([N:22]=[C:19]=[O:21])=[C:32]([I:33])[C:31]=1[C:41]([N:40]([CH3:43])[CH3:39])=[O:42]
Reactant: CNC(=O)c1c(I)c(N=C=O)c(I)c(NC(C)=O)c1I
Reactant: CN(C)C=O
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)C)c1I
Reaction time: 8 h

Procedure:
To glucosamine (1.97 g., 0.011 mole) and potassium carbonate (4.14 g.; 0.03 mole) in dimethylformamide (49 ml.) was added dropwise (required about 5 minutes) 3-acetamido-2,4,6-triiodo-5-isocyanato-N-methylbenzamide (III; 6.11 g.; 0.01 mole) dissolved in dimethylformamide (20 ml.). After being stirred overnight, the reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in water (64 ml.) and the aqueous solution was adjusted to pH 1 with concentrated hydrochloric acid. The solution was extracted with aqueous 90% phenol (4 × 25 ml.). The combined, phenolic layers were washed with water (4 × 25 ml.), diluted with ether (300 ml.) and extracted with water (4 × 25 ml.). The combined aqueous layers were washed with chloroform-isopropyl alcohol (3:1; 5 × 100 ml., contact time 15 min.), treated with "Darco G-60" (0.25 g.) overnight, and evaporated under reduced pressure at 40° C. (water bath), to give 3-acetamido-5-{3-[2-D-gluco-2-deoxy-3,4,5,6-tetrahydroxy-1-oxohexyl]ureido}-2,4,6-triiodo-N-methylbenzamide (IV) as a faint-yellow foam, 5.08 g. (64.5%), m.p. 186°-251° C. (dec.). The infrared and nuclear magnetic resonance spectra were consistent with the assigned structure. The material was homogeneous by thin-layer chromatography (chloroform-methanol-triethylamine, 65:35:5) and the aqueous solubility was determined to be 18-20% (w/v).
Reaction SMILES: Cl[C:2]1[C:14]2[CH:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:14]2[CH:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: C1COCCN1
Reactant: CC1(C)OCCn2c1cc1c(Cl)nc(Cl)nc12
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1cc1c(N3CCOCC3)nc(Cl)nc12
Yield: 40 %

Procedure:
Cesium carbonate (1.2 g, 3.7 mmol) and 1,2-dibromoethane (316 μL, 3.7 mmol) were added to a solution of 2-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 1.23 mmol) in DMF (4 mL) and the reaction mixture was heated at 100° C. for 45 min, then partitioned between water and ethyl acetate. The organic extract was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene. A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (1.23 mmol), morpholine (236 μL, 2.69 mmol) and triethylamine (342 μL, 2.46 mmol) in IMS (3 mL) was heated at reflux for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (159 mg, 40%). LCMS (method A): RT=3.13 min, [M+H]+=323.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:45](=[O:46])[C:44]([S:43][CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:48]([OH:49])[CH:14]=2)[CH:8]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(-c2cccc(-c3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2.00 g, 10.21 mmol), trimethylsilyltriflate (2.36 mL, 12.24 mmol), triethylamine (2.84 mL, 20.40 mmol), methylene chloride (26 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 93°-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.79 (t, 2 H), 3.01 (t, 2 H), 6.92 (s, 1 H), 7.21 (m, 5 H), 7.42 (t, 1 H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.75 (d, 2 H), 7.82 (t, 2 H), 8.02 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-fluoro-4-methyl-benzoic acid (Aldrich, 3.08 g, 20 mmol) in diethyl ether (30 mL), oxalyl chloride (2.85 mL, 30 mmol) was added slowly followed by a drop of N,N-dimethylformamide. The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure to give 3-fluoro-4-methyl-benzoyl chloride that was used directly for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1)([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: O=C1CN(Cc2cccc([N+](=O)[O-])c2)S(=O)(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CC(=O)NS2(=O)=O)c1

Procedure:
To a solution of the title C compound in Example 5, 5-(3-nitrobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (30 mg, 0.11 mmol) in EtOH (5 mL) is added palladium on carbon (10 mg) and the mixture is stirred under 1 atm of hydrogen for 1 h. The catalyst is removed by filtration through a plug of Celite which is washed with MeCN/water (1:1), (20 mL). The solvents are evaporated to afford 5-(3-Aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a brown solid: [M−1]−=240.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Methane sulphonyl chloride (0.11 ml, 1.4 mmol) was added to a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.25 g, 1.24 mmol) and 4-(dimethylamino)pyridine (0.167 g, 1.4 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour and then 4-(dimethylamino)pyridine (0.051 g, 0.42 mmol) and methane sulphonyl chloride (0.033 ml, 0.42 mmol) were added and the mixture stirred at room temperature for a further 1 hour. The mixture was purified directly by silica gel chromatography, eluting with a 3:1 to 1:1 mixture of iso-hexane:ethyl acetate to yield tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 94% yield):
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CCCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]=2)[CH3:10])=[N:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N3CCOCC3)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Temperature: 140 °C

Procedure:
A mixture of 6-chloro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 37; 174 mg, 0.5 mmol), morpholine (0.8 ml) and DIEA (0.13 ml) in n-BuOH (3 ml) was heated to 140° C. for 4 hrs. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% acetonitrile/H2O, 15 min) to give the title compound as solid (103 mg). 1H NMR: 11.09 (s, 1H), 9.21 (s, 1H), 8.36-8.66 (m, 1H), 7.74 (ddd, 1H), 7.55 (dd, 1H), 5.80-5.84 (m, 1H), 5.73 (s, 1H), 5.01-5.21 (m, 1H), 3.10-3.81 (m, 8H), 2.24 (s, 3H), 1.50 (d, 3H); m/z 399.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.Cl.[CH3:36][N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][CH:40]([CH2:45][C:46]1[CH:47]=[C:48]([C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=3)[CH:49]=[CH:50][CH:51]=1)[CH2:41]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:59][CH2:58][C:54]4[CH:53]=[C:52]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([CH2:45][CH:40]6[CH2:39][CH:38]7[N:37]([CH3:36])[CH:42]([CH2:43][CH2:44]7)[CH2:41]6)[CH:47]=5)[CH:57]=[CH:56][CH:55]=4)=[O:28])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1C2CCC1CC(Cc1cccc(-c3cccc(CN)c3)c1)C2
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CC5CCC(C4)N5C)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.045 g, 0.1 mmol) in DMSO (0.5 mL) was added 1-{3′-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)methyl]-3-biphenylyl}methanamine dihydrochloride (0.047 g, 0.12 mmol), HBTU (0.054 g, 0.15 mmol), and TEA (0.042 mL, 0.3 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was purified using a Gilson HPLC (with 0.1% TFA), concentrated, basified with amino cartridge to afford 0.0409 g (52%) of the title compound. LC-MS m/z 754 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[Li]CCCC.[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1.Cl>C1COCC1.O>[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]([C:11]3[NH:10][C:18]4[C:13]([CH:12]=3)=[CH:14][CH:15]=[CH:16][N:17]=4)[OH:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1cc2cccnc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a cold solution of 1-phenylsulfonyl-7-azaindole (1.29 g, 5 mmol) in 250 ml of THF was added at -30° C. n-BuLi (2.5M in hexane, 4 ml, 10 mmol). The mixture was stirred at -30°-40° C. for 1 h and then cooled to -50° C. To the above mixture was added dropwise at -50° C. a solution of 4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]butyraldehyde (1.37 g, 5 mmol) in 25 ml of THF, and the mixture was stirred at -40°-50° C. for 1 h and then allowed to warm to -5° C. for 2 h. Water was added to the mixture, and the resulting reaction mixture was acidified with 1N HCl solution, and then re-basified with an aqueous sodium bicarbonate solution, extracted with methylene chloride, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/5-1/0; then methylene chloride/acetone 2/1-1/1) followed by recrystallization from methylene chloride/methanol to afford 501 mg (25%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-7-azaindole, as a white crystalline solid, m.p.166°-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9]Br)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[O:13])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: Oc1ccccn1
Reactant: COc1ccc(CCBr)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(CCn2ccccc2=O)cc1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
Into a 100 mL round bottom flask was added 2-bromo-4-(2-bromo-ethyl)-1-methoxy-benzene (I-165, 1.82 g, crude), 2-hydroxypyridine (258 mg, 2.72 mmol), K2CO3 (625 mg, 4.53 mmol), and DME (20 mL). After stirring for 18 hours at 80° C. the suspension was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with 25-50% acetone/hexanes to afford 221 mg of I-166 as a brown oil in 40% yield (2 steps).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[OH-].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)C1(c2ccc3[nH]ccc3c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc3[nH]ccc3c2)CC1
Temperature: 45 °C
Yield: 87 %

Procedure:
To a solution of methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (1.74 g, 8 mmol) in CH3OH (50 m L) and water (20 mL) was added LiOH (1.7 g, 0.04 mol). The mixture was heated at 45° C. for 3 hr. Water was added and the mixture was acidified with concentrated HCl to pH ˜3 before being extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated to give 1-(1H-indol-5-yl)cyclopropanecarboxylic acid (1.4 g, 87%). 1H NMR (300 MHz, DMSO-d6) 7.43 (s, 1H), 7.30-7.26 (m, 2H), 7.04 (dd, J=1.5, 8.4 Hz, 1H), 6.35 (s, 1H), 1.45-1.41 (m, 2H), 1.14-1.10 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[N:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[OH:33].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]=2)[CH:21]=[CH:20][C:19]=1[OH:33]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Clc1cncc(NCc2cccnc2)n1
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: Cc1ccccc1
Product: COc1cc(-c2cncc(NCc3cccnc3)n2)ccc1O
Yield: 100.5 %

Procedure:
A mixture of 6-chloro-N-(pyridin-3-ylmethyl)pyrazin-2-amine (49 mg, 0.22 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.20 mmol), (PPh3)4Pd (23 mg, 0.020 mmol) and a Na2CO3 solution (0.22 mmol of a 2 M solution) in toluene (10 ml) was heated under reflux overnight. After removal of the solvents, the residue was dissolved in CH2Cl2 (150 ml), dried (Na2SO4), filtered and the CH2Cl2 removed in vacuo. The residue was purified by column chromatography, eluting with a n-hexane:ethyl acetate gradient mixture to obtain the desired product (62 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>C(#N)C>[Cl:27][C:23]1[CH:22]=[C:21]2[NH:20][C:19](=[O:28])[C:10]3([CH:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:14][C:13](=[O:15])[NH:12][CH:11]3[C:16]([CH3:18])=[CH2:17])[C:26]2=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: CC#N
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 16.2 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), methanesulfonyl chloride (0.0092 mL, 0.15 mmol), in acetonitrile (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep. HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].C(N=C=NC(C)C)(C)C>O1CCCC1>[C:12]([CH2:14][C:15]([NH:4][C:3]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1])=[O:16])#[N:13]
Reactant: N#CCC(=O)O
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
2,4-Dichloro-5-methoxyaniline (5.00 g, 26 mmol) and cyanoacetic acid (2.28 g, 26.8 mmol) were mixed in 50 mL of tetrahydrofuran until a solution formed. This solution was heated to reflux and 1,3-diisopropylcarbodiimide (4.2 mL, 26.8 mmol) was added dropwise. After 30 minutes the mixture was cooled to ˜15° C. in an ice-bath. The solid was collected by filtration and washed with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid was collected by filtration, washed with water, and was then dissolved in 500 mL of ethyl acetate. The solution was dried over sodium sulfate and concentrated in vacuo to give 5.9 g (88%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide as a white solid, mp 180-181° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 4.02 (s, 2H), 7.58 (s, 1 H), 7.66 (s, 1 H), 10.00 (s, 1 H); MS (ES) m/z257.0, 259.0 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])=[CH:5][CH:4]=1.COC1C=C[C:27]([NH2:28])=CC=1.BrCC(Br)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]([CH3:12])[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:27]2=[NH:28])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(NCC(C)Nc2ccc(OC)cc2)cc1
Agent: CC(Br)CBr
Product: COc1ccc(N2CC(C)N(c3ccc(OC)cc3)C2=N)cc1
Yield: 32.7 %

Procedure:
1,2-Bis(4'-methoxyphenyl-amino)-propane, applied as starting substance, is obtained with a yield of 32.7% by reacting 4-methoxyaniline with 1,2-dibromopropane as described by McKay and Tarlton (loc. cit.). The compound melts at 82°-84° C.