Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:8]([Br:9])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11])(=[O:3])[CH3:2]>O1CCCC1>[CH3:11][C:5]1[S:6][C:7]([CH3:10])=[C:8]([Br:9])[C:4]=1[C@H:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1c(C)sc(C)c1Br
Solvent: C1CCOC1
Product: Cc1sc(C)c([C@@H](C)O)c1Br

Procedure:
3-Acetyl-4-bromo-2,5-dimethylthiophene (78.5 mmol) was reduced by means of Ipc2BCl in tetrahydrofuran using the general method of Brown et al. (J. Org. Chem. 1989, 54, 4504).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([N:20](C(C5CC5)=O)[C:21]([CH:23]5[CH2:25][CH2:24]5)=[O:22])[N:19]=4)[N:16]=3)[C:6]=2[CH:31]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.O1CCOCC1>C([O-])([O-])=O.[Na+].[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].C(Cl)Cl>[CH3:32][N:33]1[CH:37]=[C:36]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[N:8][N:7]([CH2:10][C:11]4[CH:12]=[CH:13][C:14]5[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]6[CH2:24][CH2:25]6)=[O:22])[N:19]=5)[N:16]=4)[C:6]=3[CH:31]=2)[CH:35]=[N:34]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(C1CC1)N(C(=O)C1CC1)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3nnn(Cc4ccc5nc(NC(=O)C6CC6)cn5n4)c3c2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 135.9 %

Procedure:
A mixture of N-(6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide 13E (0.7 g, 1.457 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.303 g, 1.457 mmol) and PdCl2(dppf)-CH2Cl2 (0.06 g, 0.075 mmol) in Na2CO3 (2N, 6 mL)/dioxane (12 mL) was heated in a microwave at 110° C. for 45 min. The reaction was filtered and rinsed with EtOAc. This reaction was repeated twice. The organic solutions were combined and washed with 5% citric acid followed by NaHCO3, dried with MgSO4, and filtered. MeOH was added to the EtOAc solution to give 5% MeOH (v/v), and the resulting solution was filtered through a short silica column and rinsed thoroughly with 5% MeOH/EtOAc. Activated charcoal (1 g) was added to the eluent and stirred at ambient temperature for 1 hr. The solution was filtered through Celite and concentrated to dryness via rotary evaporation. The resulting material was suspended in EtOAc (50 mL) and sonicated. The resulting solid was collected by filtration and rinsed with EtOAc to provide the title compound, N-(6-((6-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide 13 (820 mg, 1.98 mmol, 45%). The filtrate was concentrated and reconstituted in 10% MeOH/EtOAc, loaded on a short silica column and eluted with 10% MeOH/EA to give provide additional product (190 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.86 (m, 4 H) 1.88-1.97 (m, 1 H) 3.88 (s, 3H) 6.15 (s, 2 H) 7.12 (d, J=9.35 Hz, 1 H) 7.66 (dd, J=8.72, 1.39 Hz, 1 H) 7.93-8.01 (m, 2 H) 8.04 (d, J=8.84 Hz, 1 H) 8.10 (s, 1 H) 8.17 (s, 1 H) 8.26 (s, 1 H) 11.18 (s, 1 H). MS:m/z 414.2 (M+H)+. MP 250.2-251.6° C.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH2:7][C:8]1[NH:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:9]=1.[OH-].[K+]>>[NH2:1][N:12]1[C:8]([NH2:7])=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:11]1
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Product: Nc1cc(-c2ccc(F)cc2)nn1N
Temperature: 80 °C
Yield: 14.9 %

Procedure:
Hydroxylamine-O-sulfonic acid (2.26 g, 20-0 nmol) was portionwise added to aqueous solution, (100 mL) containing 5-amino-3-(4-fluorophenyl)-1H-pyrazole (2.0 g, 11.3 mmol) and potassium hydroxide (2.52 g, 45 mmol) while stirring at 80° C. After the mixture was stirred at 80° C. for 30 minutes, potassium hydroxide (2.52 g, 45 mmol) was added thereto, hydroxylamine-O-sulfonic acid (2.26 g, 20.0 mmol) was portionwise added, and the mixture was stirred for further 1 hour. The reaction solution was cooled down to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous potassium carbonate, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (C-300, hexane:ethyl acetate=1:2) to obtain the title compound (324 mg, 14.9%).
Reaction SMILES: O=[C:2]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH:6]=[CH:5][CH2:4]2.[OH-:19].[Na+].OO>C1COCC1>[OH:19][CH:5]1[CH2:6][CH2:7][C:3]2([CH2:8][CH2:9][CH2:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]2)[CH2:4]1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC=CC2)C1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(CCC(O)C2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
To a solution of tert-butyl 6-oxo-7-azaspiro[4.5]dec-2-ene-7-carboxylate (0.61 g, 2.44 mmol) in anhydrous THF (5 mL) was added borane-methyl sulfide complex (10.0 M, 2.45 mL, 24.5 mmol) at 0° C. After stirring for 10 min, the reaction mixture was warmed to rt and stirred overnight, then cooled down to 0° C. and a mixture of NaOH aqueous solution (3 M, 3 mL, 9 mmol) and H2O2 (30% in water, 3 mL) was added. After stirring for 5 min, the reaction mixture was heated to reflux for 5 h, then cooled down to rt and concentrated in vacuo. The residue was dissolved in water (10 mL), and extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (50 mL), and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as colorless oil (252 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12]C(=O)C)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(NC(C)=O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)ccc1[N+](=O)[O-]
Yield: 102.5 %

Procedure:
A mixture of N-(3-methoxy-4-nitro-phenyl)-acetamide (16.6 g, 78.67 mmol) and an aqueous solution of hydrochloric acid (1.5 M, 200 mL) was refluxed until a clear solution was obtained. The reaction mixture was basified by addition of an aqueous solution of potassium carbonate and then was extracted four times with dichloromethane (200 mL); the combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 13.56 g (quantitative yield) of 3-methoxy-4-nitro-phenylamine as a yellow solid. MS=169 [M+H]+.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH:6]1[CH2:8][CH2:7]1)([O-:3])=[O:2].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][SH:11]>C1COCC1>[CH:6]1([CH:5]([S:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][N+:1]([O-:3])=[O:2])[CH2:8][CH2:7]1
Reactant: CCOC(=O)CS
Reactant: O=[N+]([O-])/C=C/C1CC1
Solvent: C1CCOC1
Product: CCOC(=O)CSC(C[N+](=O)[O-])C1CC1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
(E)-(2-Nitrovinyl)cyclopropane (4-11, 750 mg, 6.63 mmol) was taken up in THF (20 mL). To this was added ethyl thioglycolate (0.88 mL, 7.98 mmol) then TEA (1.2 mL, 8.61 mmol) at rt. After stirring overnight the mixture was concentrated. The crude product was subjected to silica gel chromatography (40 g, 0-20% EtOAc/hexanes, 10 minute gradient) to afford ethyl 2-((1-cyclopropyl-2-nitroethyl)thio)acetate (4-12, 1.46 g, 94%) as a clear oil. 1H NMR (399 MHz, CDCl3): δ 4.73-4.58 (m, 2H); 4.21 (q, J=7.1 Hz, 2H); 3.34 (d, J=6.2 Hz, 2H); 2.93 (dt, J=9.9, 7.2 Hz, 1H); 1.30 (t, J=7.1 Hz, 3H); 1.00-0.90 (m, 1H); 0.69 (dd, J=8.0, 1.6 Hz, 2H); 0.47-0.36 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(N)c1N
Yield: 101.9 %

Procedure:
2-Amino-3-nitroanisole (4.3 g) was hydrogenated in ethyl acetate (200 ml) using catalytic 10% palladium on charcoal under an atmosphere of hydrogen at ambient temperature. Once complete the reaction mixture was filtered through Celite and the filtrate evaporated in vacuo to afford the title compound as a brown liquid (3.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12](#[N:14])[CH3:13]>CCOCC.O.CO.C(O)(C)C>[NH2:7][C:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:13][C:12]#[N:14]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: N#CC=C(N)c1ccc(Cl)cc1

Procedure:
To a mixture of 68.5 g. of p-chlorobenzonitrile and 24.0 g. of sodium hydride (50% in mineral oil) in 250 ml. of ether is added, 26.1 ml. of acetonitrile and 2 ml. of isopropanol. The mixture is stirred and refluxed on a steam bath for 6 hours and then stirred overnight at room temperature. A 5 ml. portion of methanol and 250 ml. of water are added. The ether is boiled away on a steam bath and the mixture is filtered. The solid is dissolved in warm ethyl acetate and filtered. The filtrate is evaporated to a solid giving β-amino-4-chlorocinnamonitrile.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:29])([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CC#N>[CH3:29][C:26]([NH:28][S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5])([CH3:27])[CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[N:16]=[CH:17]2
Reactant: CC(C)(N)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(NS(=O)(=O)C1CC1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Cyclopropanesulfonyl chloride (155 μl, 1.52 mmol) was added to 1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-methyl-1-phenylpropan-2-amine (26a, 0.070 g, 0.19 mmol) triethylamine (80 μl, 0.57 mmol) in MeCN (3 ml) at room temperature. The reaction mixture was stirred over night, concentrated, diluted with 10% NaHSO4 (aq) and extracted with EtOAc. The organic phase was washed with 10% NaHSO4 (aq). The crude product was further purified by HPLC. Yield 25 mg (30%).
Reaction SMILES: N#N.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([I:25])C(=O)C1.CCO>CCOC(C)=O>[I:25][C:15]1[N:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=3)=[CH:10][C:11]2=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Ic1cnc2cc(-c3ccncc3)ccn12

Procedure:
Charge a 250 μL round bottom flask equipped with: a magnetic stirrer, temperature controlled heating mantle, N2 atmosphere, with 7-pyridin-4-yl-imidazo[1,2-a]pyridine (3.35 g, 17.2 mmol), NIS (3.8 g, 16.8 mmol), EtOH (3A). Heat the reaction to 65° C. for 1 hour. This can be followed by SiO2 TLC (100% EtOAc). Add more NIS (3.8 g, 16.8 mmol) and heat the reaction to 65° C. for 1 hour. Mix the reaction while cooling in an ice bath for 30 minutes then filter and rinse the solids with MeOH. Air dry the solids and vacuum oven dry at 40° C. to afford 4.59 g (83%). Additional product can be obtained from the filtrate. MS (ES), m/z 322 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([CH:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=2[OH:25])[CH3:16])[C:9]=1[OH:26].[Br:29]Br>C(O)(=O)C>[Br:29][C:4]1[C:5]([OH:28])=[C:6]([CH:27]=[C:2]([Cl:1])[CH:3]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([CH:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=2[OH:25])[CH3:16])[C:9]=1[OH:26]
Reactant: BrBr
Reactant: CC(c1cc(Cl)cc(Cl)c1O)c1cc(F)cc(Cc2cc(Cl)ccc2O)c1O
Solvent: CC(=O)O
Product: CC(c1cc(Cl)cc(Cl)c1O)c1cc(F)cc(Cc2cc(Cl)cc(Br)c2O)c1O

Procedure:
2-(5-Chloro-2-hydroxybenzyl)-6-[1-(3,5-dichloro-2-hydroxyphenyl) ethyl]-4-fluorophenol was brominated using bromine in acetic acid at room temperature to give the title compound; m.p. 171°.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[CH:1]([CH:4]1[NH:8][C:7](=[O:9])[N:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)C1NC(=O)NC1=O
Product: COc1ccc(CN2C(=O)NC(C(C)C)C2=O)cc1

Procedure:
Using 5-isopropylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.29 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (2.72 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][C:11](=[O:18])[C:10]=2[C:9]([CH3:19])=[N:8]1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][CH:14]1[C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[C:9]([CH3:19])[C:10]=2[C:11](=[O:18])[CH2:12][C:13]1([CH3:16])[CH3:17]
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Br
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.25 g, 0.98 mmol), prepared as described in example 3, and N-bromosuccinimide (0.180 g, 0.98 mmol) in chloroform (6 ml) was stirred at 60° C. for about 4 hours and then washed with water. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10). The title compound was obtained as a colourless solid (0.28 g, 85%): m.p 160-161° C.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4]CCCC)[CH3:2].O>C(O)CCC.O>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:4])[OH:9])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCCN
Solvent: CCCCO
Solvent: O
Product: CCP(=O)(O)CCCN
Reaction time: 4 h
Yield: 97.9 %

Procedure:
414 g (2 mol) of butyl ethyl(3-aminopropyl)phosphinate (produced as in Example 14) are initially charged to a 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. At 160° C., during 4 h, 500 ml of water are metered in and a butanol-water mixture is distilled off. The solid residue is recrystallized from acetone to obtain 296 g (98% of theory) of ethyl(3-aminopropyl)phosphinic acid as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1N
Reactant: COc1ccc(C=O)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(OC)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-methoxy benzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.33 (s, 1H), 7.78 (d, 2H, J=8.8 Hz), 7.13 (d, 1H, J=2.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.87 (d, 1H, J=1.8 Hz), 3.87 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].COCO[C:12]1[CH:13]=C(C=[CH:18][CH:19]=1)CCl>CN(C=O)C>[CH2:1]([S:5][CH2:13][CH2:12][CH2:19][CH3:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: COCOc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
n-Butanethiol (0.69 mL, 6.4 mmol) was added dropwise to a cold suspension of NaH (60% oil dispersion, 307 mg, 7.7 mmol) in DMF (10 mL). After 30 min, the resulting solution was treated with 3-methoxymethoxybenzyl chloride (40) (595 mg, 3.2 mmol) and stirred for an additional hour at room temperature. The reaction mixture was quenched with saturated NH4Cl and extracted with ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash chromatography eluting with 1% AcOEt-Hexanes to yield n-butylsulfide 42 (248 mg, 32%). 1H NMR (400 MHz, CDCl3) δ: 0.90 (t, J=7.3 Hz, 3H, —CH3), 1.40 (m, 2H, —CH2—CH2), 1.56 (m, 2H, —CH2—CH2), 2.44 (t, J=7.5 Hz, 2H, —CH2—S), 3.50 (s, 3H, OMe) 3.69 (s, 2H, —CH2—S), 5.20 (s, 2H, —CH2—O), 6.96 (d, J=7.2 Hz, 1H, Ar), 6.98 (d, J=7.3 Hz, 1H, Ar), 7.01 (s, 1H, Ar), 7.24 (t, J=7.8 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][CH2:18][Cl:19]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)O)c(N)cc1OCCCCl
Temperature: 40 °C
Yield: 102.1 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 2.04 g (6.90 mmol) of 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoic acid (purity: 99%) obtained in Reference Example III-8 and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.2 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 2 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 1.83 g (isolated yield: 97.0%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of 5-methoxy-4-(3-chloropropoxy)anthranilic acid as a white crystalline product.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[NH:3]1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:3]1[C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[C:2]1=[O:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1ccc(-n2c(=O)[nH]c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)cc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of ethyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate from Step C (590 mg, 2.09 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (104 mg of a 60% dispersion in mineral oil, 2.60 mmol). The mixture was stirred for 5 min, then tert-butyl bromoacetate (489 mg, 2.51 mmol) was added and stirring was continued for 3 h. The reaction mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with H2O (50 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=397 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cn1ncc2c(-c3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4[nH]ncc34)nc21
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 4-(methanesulfonyl)benzene boronic acid (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 115. NMR (CDCl3): 3.19 (3H, s), 4.36 (3H, s), 7.58 (1H, m), 7.67 (1H, d), 7.84 (1H, d), 7.87 (1H, s), 8.06 (2H, d), 8.19 (1H, s), 8.20 (2H, d), 8.96 (1H, s), 10.20 (1H, br). MS: MH+ 404
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:33][CH:34]2[CH2:36][O:35]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][CH:34]2[CH2:36][O:35]2)=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CO2)c(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of compound 4-bromo-2-(1H-indol-2-yl)phenol (1 g, 3.48 mmol) in DMF (35 mL) was added CsF (1.59 g, 10.45 mmol) and oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.81 g, 6.97 mmol). The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with water and brine. The crude product was purified using chromatography (petroleum ether:EA=14:1) to provide compound 2-(5-bromo-2-(oxiran-2-ylmethoxy)phenyl)-1H-indole (1 g, yield: 84.0%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.33 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.38˜7.44 (m, 2H), 7.07˜7.12 (m, 3H), 6.97 (t, J=7.2 Hz, 1H), 4.49˜4.53 (m, 1H), 3.97˜4.01 (m, 1H), 3.46˜3.49 (m, 1H), 2.88 (t, J=4.4 Hz, 1H), 2.74˜2.76 (m, 1H). MS (M+H)+: 344/346.