Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[P:33](=[O:40])([O:37]CC)[O:34][CH2:35][CH3:36])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[P:33](=[O:37])([OH:40])[O:34][CH2:35][CH3:36])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 45 °C
Yield: 64.2 %

Procedure:
A solution of intermediate 187, diethyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate (0.115 g, 0.20 mmol) in tetrahydrofuran (3 ml)/ethanol (3 mL) was treated with 1 N aqueous sodium hydroxide (1.0 ml, 1.0 mmol) and the resulting mixture heated at 45° C. for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified on a Shimadzu automated preparative HPLC system (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) to give 0.070 g (64% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ ppm: 1.37 (3H, t, J=7.1 Hz, CH3), 1.62 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.18 (2H, m, OCH2), 4.75 (2H, broad d, J=5 Hz, NCH2), 5.32 (2H, s, OCH2), 7.21 (1H, m, aromatic), 7.30-7.33 (3H, m, aromatics), 7.38-7.40 (2H, m, aromatics), 7.47-7.52 (1H, m, aromatic), 7.56-7.63 (1H, m, aromatic), 8.56 (1H, broad t, NH). HRMS (ESI+) calculated for C26H30FN3O7P [M+H+]: 546.1805; found: 546.1786.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][CH:17]=1>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:22]([CH2:23][CH3:24])([OH:25])[C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: Clc1cccc(Br)c1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(O)(c1ccc(O)cc1)c1cccc(Cl)c1

Procedure:
To a Grignard reactant prepared from 14.6 g. of magnesium turnings and 115 g. of 3-chloro-bromobenzene in 350 ml. of dry tetrahydrofurane a solution of 30.1 g. of 4'-hydroxy-propiophenone in 540 ml. of dry tetrahydrofurane is added dropwise, with stirring under slight reflux. The reaction mixture is slightly boiled for 30 additional minutes, cooled and decomposed by pouring onto a mixture of ice and glacial acetic acid. After separation the organic phase is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Crystallization of the solid residue from a mixture of n-hexane and ethyl acetate yields 42.6 g. of the named compound, melting at 132° to 134° C.
Reaction SMILES: C[O:2]CCNC.[C:7]([O:10][C:11](=O)[CH3:12])(=O)C.[N:14]1[CH:19]=CC=[CH:16][CH:15]=1>>[CH3:7][O:10][CH2:11][CH2:12][N:14]([CH3:19])[C:15](=[O:2])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CNCCOC
Reactant: c1ccncc1
Product: COCCN(C)C(C)=O
Reaction time: 24 h

Procedure:
Dissolve N-(2-methoxyethyl)methylamine (5.81 g, 65.18 mmol) in 40 mL of pyridine at 0° C. and add acetic anhydride dropwise. After 30 minutes raise the reaction to room temperature and stir for 24 hours. Remove the solvent in vacuo and dissolve the residue in methylene chloride and wash with 5N HCl. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 4.23 g of crude N-(2-methoxyethyl)-N-methylacetamide. Dissolve this crude material (4.23 g, 32.25 mmol) in 50 mL of toluene and add Lawesson's reagent (6.5197 g, 16.12 mmol) to the mixture. Heat the reaction to 75° C. and allow it to stir for 18 hours. Remove the solvent in vacuo. Triturate the residue with a 1:1 mixture of diethyl ether/pentane three times decanting carefully from the residual solids. Combine the decanted layers and remove the solvent in vacuo to afford 2.13 g of crude N-(2-methoxyethyl)-N-methylthioacetamide. Dissolve this crude material (2.13 g, 14.47 mmol) in 50 mL diethyl ether and add methyl trifluoromethanesulfonate (2.49 g, 15.19 mmol) and allow the reaction to stir for 21 hours. Decant the diethyl ether from the oil and triturate the oil with diethyl ether (3×). Remove any excess diethylether from the oily residue in vacuo to obtain 2.92 g of crude triflic acid salt of (2-methoxyethyl)methyl(1-methylsulfanylethyl)amine as a black oil. Dissolve this black oil (2.92 g, 9.38 mmol) in 50 mL of pyridine and add (R)-(6-amino-2(R)-hydroxyindan-1-yl)carbamic acid tert-butyl ester (2.46 g, 9.31 mmol) and allow the reaction to stir at room temperature for 23 hours. Remove the solvent in vacuo and dissolve the residue in methylene chloride and wash with saturated aqueous sodium hydrogencarbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo. Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc) to afford 1.304 g of the titled product (37% yield). MS (ES): m/z 378.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>[Pd].[OH-].[NH4+]>[CH3:14][O:13][C:11]1[CH:12]=[C:4]([NH2:1])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(N)c1
Yield: 86.2 %

Procedure:
A mixture of 2-nitro-4-methoxybenzoic acid (21.9 g, 0.111 mol), 2N ammonium hydroxide (250 ml) and 5% palladium on strontium carbonate (2.5 g) is shaken under 45 psi of hydrogen pressure for 3-4 hours. The reaction mixture is filtered, and the filtrate is acidified with acetic acid. A solid forms which is collected by filtration, washed with water and dried to afford 16 g of 4-methoxyanthranilic acid, m.p. 194°-195° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.[CH3:20][CH:21]([CH3:25])[C:22](Cl)=[O:23]>C1COCC1.CCCCCC>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:22](=[O:23])[CH:21]([CH3:25])[CH3:20]
Reactant: COCOc1cccc(OCOC)c1
Reactant: CC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
1,3-bis{[(methyloxy)methyl]oxy}benzene (Intermediate 35, 2.2 g) was dissolved under nitrogen in THF (8.0 mL) and a solution of BuLi (8.32 mL of a 1.6 M solution in hexane, 13.3 mmol) was added. After stirring at room temperature for 1 hour, cooling down to −78° C., 2-methylpropanoyl chloride (4.65 ml, 44.4 mmol) was added and the reaction mixture was stirred at that temperature for 1 hour. After quenching with water, the reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was then charged on a silica gel column (Biotage SP1 system) and eluted with Cyclohexane/EtOAc (from all 10/0 to 9/1, then 9/1, then from 9/1 to 8/2, then 8/2) to afford the title compound (825 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[CH3:15])[CH3:2].N1C=CC=CC=1.[Br:22]Br>ClCCl>[Br:22][C:10]1[C:9]([CH3:14])=[C:8]([CH3:15])[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][C:11]=1[CH3:13]
Reactant: CCOCCOc1cc(C)cc(C)c1C
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOCCOc1cc(C)c(Br)c(C)c1C
Temperature: 0 °C
Yield: 102.4 %

Procedure:
To a mixture of 1-(2-ethoxyethoxy)-2,3,5-trimethylbenzene (1.0 g, 4.08 mmol), pyridine (0.097 mL, 1.20 mmol) and dichloromethane (10 mL) was added a solution of bromine (0.66 g, 4.12 mmol) in dichloromethane (1 mL) under stirring at 0° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1-hexane/ethyl acetate=4/1) to give the title compound (1.2 g, yield 99%) as a colorless oil.
Reaction SMILES: [N:1]#[C:2][Br:3].[Cl:4][C:5]1[C:6]([NH:13][NH2:14])=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1.C(O)(C)C>ClCCl.C(OCC)C>[BrH:3].[NH2:1][C:2]1[N:7]2[C:8]([S:11][CH3:12])=[N:9][CH:10]=[C:5]([Cl:4])[C:6]2=[N:13][N:14]=1
Reactant: CSc1ncc(Cl)c(NN)n1
Reactant: N#CBr
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCOCC
Product: Br
Product: CSc1ncc(Cl)c2nnc(N)n12

Procedure:
A solution of 40 mL (120 mmol) of 3 molar cyanogen bromide in dichloromethane was combined with 19.0 g (100 mmol) of 5-chloro-4-hydrazino-2-methylthiopyrimidine and 200 mL of dry isopropyl alcohol at ambient temperature with stirring. The resulting mixture was stirred for 18 hours and then diluted with 500 mL of diethyl ether. The solids that formed were recovered by filtration and dried to obtain the theoretical amount of the title compound as a yellow solid melting above 250° C. 1H NMR (DMSO-d6): δ 7.80 (s, 1H); 2.67(s, 3H); 13C: δ 150.96, 147.90, 143.10, 138.38, 113.16, 14.22. Anal. Calc'd for C6H7N5BrClS: C, 24.3; H, 2.38; N, 23.6; S, 10.8. Found: C, 26.1; H, 2.69; N, 24.0; S, 12.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@H:22]([C@@H:27]4[O:31]C(C)(C)O[C:28]4=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:36][OH:37]>CC(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@H:27]([OH:31])[C:28]([NH:36][OH:37])=[O:34])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of (5S)-5-((1S)-1-{[(2R)-4-(4′-fluorobiphenyl-4-yl)-2-methylpiperazin-1-yl]carbonyl}-3-methylbutyl)-2,2-dimethyl-1,3-dioxolan-4-one (230 mg, 0.48 mmol, 1.0 eq) in a mixture of iPrOH (4 mL) and THF (4 mL) was added a 50% aq. solution hydroxylamine (0.08 mL, 1.43 mmol, 3.0 eq). The reaction mixture was stirred at rt for 8 h. Evaporation of the solvent gave a white solid. This product was washed with iPr2O (2×), filtered and dried under vacuum to give the title compound as a white powder (89%). M−(EST): 456.3; M+(ESI): 458.4. HPLC (Condition A), Rt: 3.9 min (HPLC purity: 97.5%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:50]I)[CH2:48]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1.CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH3:48])[CH3:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(CI)(CI)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOc1ccc(Cc2cc([C@@H]3OC(C)(C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 120 °C
Yield: 147.7 %

Procedure:
To a solution of (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-bis-iodomethyl-tetrahydro-pyran (100 mg, 0.10 mmole) in toluene (2 mL), tristrimethylsilllylsilane (0.1 mL), AIBN (12 mg) was added and heated at 120° C. for 24 hour in a sealed tube. The reaction mixture was diluted with methanol and evaporated, washed with water (10 mL) and extracted with Ethyl acetate (3×15 mL). The crude product obtained after the removal of solvent to furnish 100 mg of crude (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-dimethyl-tetrahydro-pyran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[CH:73][CH:72]=1)([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:72]=[CH:73][C:74]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:75][CH:76]=1)([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA (110 uL, 0.62 mmol) and 4-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 55 mg.
Reaction SMILES: [C:1]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S(C)C.Cl>C1COCC1>[C:1]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@@H]1c1ccccc1
Yield: 102.4 %

Procedure:
To a stirred solution of N-Boc-5-(R)-phenyl-(2S)-proline (1.14 g, 3.91 mmol) in THF (20 ml) was added 10M-BH3.Me2S (780 ml, 7.82 mmol) at rt, and the resulting mixture was heated under reflux for 30 min. The mixture was poured into aq. 1N-HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3—MeOH (10:1) as eluent to give N-Boc-2-(S)-hydroxymethyl-5-(R)-phenylpyrrolidine (1.11 g, quant.) as a colorless oil: 1H-NMR (CDCl3) δ1.19 (brs, 9 H), 1.65 (brs, 1 H), 1.83-1.90 (m, 1 H), 1.98-2.06 (m, 1 H), 2.22-2.31 (m, 1 H), 3.75-3.86 (m, 2 H), 4.16-4.19 (m, 1 H), 4.83 (t, J=6.8 Hz, 1 H), 4.89 (brs, 1 H), 7.19-7.31 (m, 5 H); MS (ESI) m/z, 2.78 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O.CCOCC>CC#N>[F:14][C:10]1[C:3]([O:2][CH3:1])=[C:4]([C:7]([O:11][CH3:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: F[B-](F)(F)F
Reactant: COc1cccc(OC)c1C=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: COc1ccc(F)c(OC)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Commercially available 2,6-dimethoxybenzaldehyde (3.500 g; 21.10 mmol) was added to a suspension of Selectfluor (8.208 g; 23.20 mmol) in MeCN (35 ml), and the resulting mixture was stirred at rt, under nitrogen, for 16 h. Water and Et2O were added and the aq. layer was further extracted with Et2O. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=4/1) afforded 3-fluoro-2,6-dimethoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 185.10 g/mol.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:13]([C:15]3[C:19]4=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]4[NH:17][CH:16]=3)=[CH:14][C:7]=12>CN(C=O)C.CCOC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:13]([C:15]3[C:19]4=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]4[N:17]([CH3:3])[CH:16]=3)=[CH:14][C:7]=12
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
Add KOH (5.0 equiv., 21.6 mg) then MeI (5.0 equiv., 55.0 mg, 24 μL) to bisazaindole 28 (37.3 mg, 0.0772 mmol) stirred in DMF (5.0 mL) at 0° C., and stir the reaction medium at for 1.5 h. Then allow the reaction medium to return to room temperature, dilute it with EtOAc, wash it with saturated NaHCO3, dry (MgSO4) and concentrate, to obtain 29 (40 mg, 100%) as an amorphous solid: TLC (EtOAc at 40%/heptane) Rf=0.10.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC=CC=1.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)[CH:20]=2)[NH:15][CH:14]=1.[H-].[Na+].CN(C)C=O>O>[CH3:1][NH:2][C:3]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[CH:18][CH:17]=2)[C:13]([CH3:12])=[CH:14]1)=[O:4]
Reactant: CNC(=O)Oc1ccccc1
Reactant: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)n1cc(C)c2cc(Oc3ccnc(N)c3)ccc21
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
Phenyl N-methylcarbamate (350 mg, Production example 2-1) was added to a solution of 4-(3-methyl-1H-5-indolyl)oxy-2-pyridinamine (500 mg), sodium hydride (93 mg) and N,N-dimethylformamide (5 ml) at room temperature; and the reaction mixture was stirred for 2 hours and 45 minutes. Water was added to the reaction mixture; extraction was performed with ethyl acetate; and purification was performed by NH-silica gel column chromatography (Fuji Silysia, hexane:ethyl acetate=1:2, sequentially, ethyl acetate) to yield the title compound as a pale yellow amorphous solid (365 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>>[ClH:21].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(Cl)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(11.5 mg, 33%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-chlorophenylsulfonyl chloride (22.5 mg, 0.11 mmol). HRMS-FAB+ for C21H18ClF3N2O2S.HCl, calculated MH+ (--HCl): 455.08078; found: 455.08266.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[NH2:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[OH:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]3[OH:21])[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 115 °C
Reaction time: 96 h
Yield: 76.2 %

Procedure:
To the solution of 2-chloro-6-methoxybenzo[d]thiazole (1.0 g, 5 mmol) in 5.5 ml of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (910 mg, 6 mmol) and DIPEA (2.44 ml, 14 mmol). The reaction solution was stirred at 115° C. for 96 hours. The crude reaction solution was purified by prep HPLC to give purified fractions that was combined and neutralized with solid NaHCO3. The resulting solution was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (60 ml) and brine (60 ml), then dried over Na2SO4 and evaporated in vacuo to give (1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1.06 g, 3.81 mmol) as an ivory solid. ES/MS m/z 279.1 (MH+).
Reaction SMILES: [I:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:9]#[N:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>[Ag-]=O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[C:4]([C:3]=1[O:11][CH3:12])[C:9]#[N:10]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1c(I)c[nH]c(=O)c1C#N
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncc(I)c(OC)c2C#N)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a mixture of 5-iodo-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (3.00 g), silver(I) oxide (2.77 g) and toluene (80 mL) was added 4-methoxybenzyl chloride (2.21 g) at room temperature, and the mixture was stirred 110° C. for 5 hr. To the reaction mixture was added 4-methoxybenzyl chloride (2.21 g), and the mixture was stirred at 110° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether, and the precipitate was collected by filtration to give the title compound (3.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#N.[CH:11]([C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[CH:18][CH:19]=1)([CH3:13])[CH3:12].C([O:24]CC)C>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:19]=1)=[O:24]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: CCOCC
Reactant: CC(C)c1cccc([Mg]Br)c1
Product: CC(C)c1cccc(C(=O)c2cc(Cl)ccc2N)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 2-amino-5-chloro-benzonitrile (1 g, 6.55 mmol) in diethyl ether (20 ml) was added 3-isopropyl phenyl magnesium bromide (prepared freshly as a 1M solution in diethyl ether; 20 ml, 19.66 mmol) drop wise at 0° C., and the resulting reaction mixture was stirred for 1 h under reflux conditions followed by another 16 h at room temperature. The reaction mixture was cooled to 5° C., quenched with water followed by 2N aqueous HCl solution. The reaction mixture was then stirred at 45° C. for an additional 5 h. The reaction mixture was made basic (pH 8-9) with aqueous solution of NaOH, and then extracted with diethyl ether (2×30 ml). The organic phases were combined and washed with brine (25 ml), dried over anhydrous Na2SO4, concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5% EtOAc in hexane) to afford (2-amino-5-chloro-phenyl)-(3-isopropyl-phenyl)-methanone (1.1 g, 61%) as a yellow sticky liquid. LC-MS (ESI): 274 (M+H)+.