Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[Br:1][C:5]1[CH:4]=[N:3][C:8]2[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: O=C1CCCc2cccnc2N1
Reactant: BrBr
Solvent: ClCCl
Product: O=C1CCCc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A 10% solution of bromine (0.57 mL, 11.1 mmole) in CH2Cl2 was added dropwise over 1 hr to a solution of 5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.20 g, 7.4 mmole) in CH2Cl2 at RT. The mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% Na2CO3 and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (EtOAc) gave the title compound (1.00 g, 56%) as a light yellow solid after drying in vacuo: MS (ES) m/e 241/243.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][F:14])[CH:11]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:34]=[N:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][F:14])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]3[CH:34]=[N:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C(CF)C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
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: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CF)C(c2ccc(-c3cnc(C#N)nc3)cc2)OC1(C)C
Yield: 47.8 %

Procedure:
To the solution of 4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]oxazolidine-3-carboxylic acid tert-butyl ester (1 g, 2.298 mmol, 1.0 eq) in toluene/water (3:1-24 mL) is added 5-Bromo-pyrimidine-2-carbonitrile (0.42 g, 2.282 mmol, 1.20 eq), Na2CO3 (0.48 g, 4.528 mmol) and degassed with nitrogen for 15 minutes followed by addition of Tetrakis(triphenylphosphine)palladium(0) (0.132 g, 0.114 mmol) and heated reaction mixture to 80° C. for 16 hours. Solvent is evaporated in vacuo to get the crude which is purified by column chromatography eluting from 10% ethyl acetate/hexane to give title compound (0.45 g): 1H-NMR (400 MHz, DMSO-d6) 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.85-3.92 (m, 1H), 4.47-4.59 (m, 1H), 4.76-4.96 (m, 1H), 5.17 (d, 1H, J=7.16), 7.67 (d, 2H, J=8.24 Hz), 7.96 (d, 2H, J=8.24 Hz), 9.40 (s, 2H).). m/z M−H 410.8.
Reaction SMILES: C(NC(=S)NC1C=CC=CC=1)CCC.[Br:15]CC(C1C=CC(Cl)=C(S(=O)(=O)N(C)C)C=1)=O.Br.[CH2:33]([N:37]1[C:41]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([S:50](=[O:55])(=[O:54])[N:51]([CH3:53])[CH3:52])[CH:44]=2)(O)[CH2:40][S:39][C:38]1=[N:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH3:63])[CH2:34][CH2:35][CH3:36]>>[BrH:15].[CH2:33]([N:37]1[C:41]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([S:50](=[O:54])(=[O:55])[N:51]([CH3:53])[CH3:52])[CH:44]=2)=[CH:40][S:39][C:38]1=[N:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH3:63])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN1C(=Nc2ccccc2C)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: Br
Agent: CCCCNC(=S)Nc1ccccc1
Product: CCCCn1c(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)csc1=Nc1ccccc1C

Procedure:
Obtained (a) by a procedure analogous to that indicated in Example 1(a), from 3-n-butyl-1-phenylthiourea and 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone, or (b) from 3-n-butyl-4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(2-methylphenyl-imino)-thiazolidin-4-ol hydrobromide. Colorless crystals; melting point 238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:17])[C:3]=1[F:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:28]1[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][C@@:36]([CH3:46])([S:42]([CH3:45])(=[O:44])=[O:43])[C:37]([O:39]CC)=[O:38])[C:30](=[O:47])[CH:29]=1.C(Cl)Cl.[Li+].[OH-].[OH-].[Na+]>O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:28]2[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][C@@:36]([CH3:46])([S:42]([CH3:45])(=[O:43])=[O:44])[C:37]([OH:39])=[O:38])[C:30](=[O:47])[CH:29]=2)=[C:4]([F:17])[C:3]=1[F:18]
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Reactant: CCOC(=O)[C@@](C)(CCn1ccc(I)cc1=O)S(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 65 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Into the THF solution of 2-(4-chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (771 mg, 2.81 mmol) was added 1.0 M K3PO4 (7.02 mL), ethyl (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (1000 mg, 2.34 mmol) and Pd(II)dppf.DCM (90 mg, 0.117 mmol, 5 mol %). The reaction mixture was stirred for 1 h at 65° C. To the reaction mixture was then added a solution of LiOH (168 mg, 7.02 mmol) in water (7.5 mL). The reaction mixture was stirred for 45 min at 55° C. The reaction mixture was treated with 1 N NaOH (4 mL) and the aqueous layer was separated and adjusted to a pH of 2 with 3 N HCl. A precipitate formed and was collected by filtration and washed with EtOAc to give the title compound as an off-white solid (0.88 g, 89.6%) LCMS m/z 420.0 (M+1). 1H NMR ppm 1.58 (s, 3 H) 2.20 (ddd, J=13.12, 10.68, 4.88 Hz, 1 H) 2.40-2.48 (m, 1 H) 3.17 (s, 3 H) 3.95 (ddd, J=12.54, 10.88, 5.66 Hz, 1 H) 4.10 (ddd, J=12.63, 10.78, 4.88 Hz, 1 H) 6.47 (dt, J=7.02, 1.85 Hz, 1 H) 6.58-6.61 (m, 1 H) 7.42-7.49 (m, 1 H) 7.52-7.58 (m, 1 H) 7.81 (d, J=7.02 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]([CH2:17][CH3:18])[CH:4]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:20]([S-:22])#[N:21].[K+].BrBr>CC(O)=O>[CH3:1][N:2]([CH3:19])[CH:3]([CH2:17][CH3:18])[CH:4]([C:10]1[CH:16]=[CH:15][C:13]2[N:14]=[C:20]([NH2:21])[S:22][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc(N)cc1)n1ccnc1)N(C)C
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step-7: A solution of 4-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)aniline (600 mg, 2.32 mmol) and KSCN (508 mg, 5.22 mmol) in 15 mL AcOH was cooled to about 7° C. and treated with Br2 (125 μL, 2.43 mmol) in 2 mL AcOH added drop-wise via syringe over 5 min. The reaction vessel was removed from the cooling bath and stirred at rt for 1 hr. The reaction was cooled in an ice bath and basified with 3N NaOH (100 mL) added portionwise over several minutes. This mixture was then extracted with DCM (4×75 mL). The combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 6% MeOH (2N NH3)/DCM to give 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine as a yellow foam. MS ESI: m/z 316.16 [M+1+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH:11]([S:14](Cl)(=[O:16])=[O:15])([CH3:13])[CH3:12].CO>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:14]([CH:11]([CH3:13])[CH3:12])(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCN2
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)S(=O)(=O)N1CCc2cc(Br)ccc21
Temperature: 100 °C
Yield: 32.9 %

Procedure:
5-Bromoindoline (0.59 g, 3 mmol) was dissolved in isopropylsulfonyl chloride (1.08 g, 7.5 mmol) and heated to 100° C. for 3 hours. The mixture was cooled and treated with methanol (10 mL) then diluted with ethyl acetate. The mixture was washed with NaHCO3, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-30% ethyl acetate in hexane) afforded 5-bromo-1-(isopropylsulfonyl)indoline (0.3 g) as a white solid. MS (EI) m/z 303.7; HPLC purity 95.8% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@:21]([NH3+:35])([C:23](=[O:34])[NH:24][C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=2)[CH3:22])=[CH:16][CH:15]=1)#[N:13].C1([O:42][C:43](=O)[NH:44][CH2:45][CH:46]([O:49][CH3:50])[O:47][CH3:48])C=CC=CC=1.CN1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C@:21]([NH:35][C:43]([NH:44][CH2:45][CH:46]([O:49][CH3:50])[O:47][CH3:48])=[O:42])([CH3:22])[C:23]([NH:24][C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=2)=[O:34])=[CH:18][CH:19]=1)#[N:13]
Reactant: COC(CNC(=O)Oc1ccccc1)OC
Reactant: C[C@@]([NH3+])(Cc1ccc(C#N)cc1)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(CNC(=O)N[C@](C)(Cc1ccc(C#N)cc1)C(=O)Nc1cc(Cl)c(F)c(Cl)c1)OC
Temperature: 65 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a solution of (R)-2-(4-cyano-phenyl)-1-(3,5-dichloro-4-fluoro-phenylcarbamoyl)-1-methyl-ethyl-ammonium toluene-4-sulfonate (87.7 g, 162.9 mmol) and (2,2-dimethoxy-ethyl)-carbamic acid phenyl ester (40.4 g, 179 mmol) in DMSO (162 mL) was added Na3PO4 (29.4 g, 179 mmol) and N-methylmorpholine (3.04 mL, 27.7 mmol). The solution was heated to 65° C. and stirred for 6 h. The solution was cooled to 20° C. and transferred to a separatory funnel with aqueous Na2CO3 (3 wt %, 500 mL) and EtOAc (500 mL), forming a triphasic system after shaking. The bottom two layers were removed. The top organic layer was washed with 3% NaCl (500 mL), dried with Na2SO4 and concentrated in vacuo keeping internal temperature lower than 40° C. A mixture of heptane and EtOAc (10:1 heptane:EtOAc, 20 mL) was added and the resulting slurry was stirred at 22° C. for 16 h. The slurry was filtered and the solids were washed with a 10:1 mixture of heptane/EtOAc (2×100 mL) to give 61.6 g of the title compound as a white solid, m/z 497.7 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25]CC)=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11].CCN(C(C)C)C(C)C>CO>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:13]1[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:23]1=[O:25]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CC2NC(=O)CNC2=O)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-methoxyphenylalaninate trifluoroacetate (598 mg, 2.13 mmol), Hünig's base (0.371 mL, 2.13 mmol), and MeOH (20 mL). The reaction mixture was stirred at 75° C. for 24 h. The mixture was allowed to cool to room temperature. The solid formed was collected by filtration and washed with MeOH to give 3-(3-methoxybenzyl)-2,5-piperazinedione (423 mg).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[Br:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:5]([CH3:22])([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:9][CH:8]=2)[C:4]([OH:33])=[O:3])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)S(=O)(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Cc1ccc(OCCN2CCCCC2)cc1)(C(=O)O)S(=O)(=O)c1ccc(Br)cc1

Procedure:
2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionic acid was prepared according to general method as outlined in example 9. Starting from 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester (6.5 g, 20 mmol), ethanol (30 mL) and 10 N sodium hydroxide (15 mL). Yield 6.3 g (100%); yellow solid mp 125-127° C.; MS 512.5 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19]C(=O)C)[CH:17]=3)[CH2:12][O:11][C:9]=2[CH:10]=1.[OH-].[Na+].[ClH:29].C(OCC)C>C(O)C.O.CO>[ClH:29].[ClH:29].[NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH2:19])[CH:17]=3)[CH2:12][O:11][C:9]=2[CH:10]=1
Reactant: CC(=O)Nc1cc2c(cn1)COc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OCc1cnc(N)cc1-2
Temperature: 90 °C
Reaction time: 14 h
Yield: 37 %

Procedure:
A stirred solution of (S)-N-(8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (40 mg, 0.113 mmol) and NaOH (45.0 mg, 1.125 mmol) in a mixture of ethanol (10 mL) and water (4 mL) was heated to 90° C. for 18 h. The volatiles were removed under reduced pressure and the residue was partitioned between water (20 mL) and dichloromethane (15 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced to pressure to afford crude (S)-8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-amine (23 mg, 0.068 mmol, 60% crude yield) which was taken in MeOH (2 mL) and cooled to 0° C. The resultant solution was treated with 1M HCl in diethyl ether (15 mL, 0.068 mmol) and the reaction was stirred at room temperature for 14 h. The reaction mixture was then cooled to 0° C. to afford a solid which was filtered, washed with diethyl ether (10 mL) and dried under vacuum to afford (S)-8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-amine dihydrochloride (11 mg, 0.025 mmol, 37% yield for two steps) as a brown solid. 1H NMR (400 MHz, MeOD) δ 7.88 (d, J=6.9 Hz, 1 H), 7.78 (s, 1 H), 7.17 (s, 1 H), 6.89 (m, 1 H), 6.75 (d, J=2.1 Hz, 1 H), 5.07 (s, 2 H), 4.84-4.34 (m, 1 H), 4.17-4.13 (m, 1 H), 3.71 (m, 1 H), 1.82-1.75 (m, 1 H), 1.73-1.66 (m, 2 H), 1.04 (m, 6 H). LCMS (ESI) m/e 314.2 [(M+H)+, calcd for C18H24N3O2 314.2]; LC/MS retention time (Method D): tR=1.1 min; HPLC retention time (method A): tR=5.16 min; HPLC retention time (method B): tR=8.96 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(O)C>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C=NCCCl
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCO
Product: O=C(NCCCl)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2 g of 6-aminoindazole in 125 mL of anhydrous ethanol is added, in a dropwise manner, 1.25 g of 2chloroethyl isocyanate. This solution is stirred for 16 h at room temperature, cooled at -20° C., and filtered. A white solid separated and was recrystallized from ethanol, yield 30%, mp 253°-258° C. 1H NMR (DMSO-d6 : CDCl3): 8.12 ppm, 7.56 ppm, 7.44 ppm, 7.25 ppm, 7.12 ppm, 7.08 ppm, 6.43 ppm, 6.39 ppm, 6.01 ppm, 5.98 ppm, 5.96 ppm, 3.42 ppm, 3.4 ppm, 3.39 ppm, 3.54 ppm, 3.26 pm, 3.23 ppm, 3.2 ppm, 3.17 ppm, 3.14 ppm, 3.12 ppm, 3.09 ppm, 3.05 ppm, 3.04 ppm, 3.04 ppm.
Reaction SMILES: [ClH:1].C([O:9][CH2:10][C:11]([N:13]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:13]([CH3:14])[C:11](=[O:12])[CH2:10][OH:9].[ClH:1]
Reactant: [H][H]
Reactant: CN(C)CCN(C)C(=O)COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCN(C)C(=O)CO
Reaction time: 8 h

Procedure:
Crude HCl salt of 101 was mixed with 201.8 mg (0.1896 mmol) of palladium on charcoal (10%) in 15 mL of methanol. The mixture was subjected to hydrogen atmosphere at 50 psi on a Parr apparatus at room temperature. After overnight, another 200.9 mg of catalyst was needed. After overnight, reaction was completed and the insolubles was filtered off through glass fiber filter paper. The filtrate was concentrated to yield 254.6 mg (quant.) of product 102 as HCl salt: 1H NMR (400 MHz, CDCl3): δ 2.89 (s, 6H), 3.06 (s, 3H), 3.21 (t, J=6.6, 2H), 3.93 (t, J=6.6, 2H), 4.25 (s, 2H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH:2]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:25])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
18 g of D-glucose are stirred in 50 ml of ethanol at 70° C., 18.5 g of dodecylamine are then added, heating is continued until the solution is clear, the mixture is left to cool to room temperature and the precipitated crystals are filtered off with suction for a further 20 hours. They are washed with ethanol and ether and dried in vacuo.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[NH2:16]>>[CH2:2]([C:1]1[NH:16][C:15]2[CH:14]=[CH:13][C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:21][CH2:22]3)=[CH:11][C:10]=2[N:9]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1N
Product: CCCCCc1nc2cc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2[nH]1
Yield: 57 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-hexanoic acid in place of butyric acid to react with [4-(3,4-diaminophenyl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a yellow syrup in 57% yield (0.347 g). 1H NMR (300 MHz, CDCl3) δ 8.8 (br., s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64-7.45 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 6.99 (s, 1H), 6.87 (dd, J=1.9, 8.7 Hz, 1H), 4.00-3.91 (m, 2H), 3.33 (t, J=4.8 Hz, 2H), 3.15 (t, J=5.1 Hz, 2H), 3.05-2.95 (m, 2H), 2.82 (t, J=7.7 Hz, 2H), 1.85-1.70 (m, 2H), 1.33-1.16 (m, 4H), 0.79 (t, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 155.3, 147.4, 138.4, 134.5, 134.0, 132.3, 129.3, 127.2, 127.1, 126.8, 126.8, 126.7, 126.6, 125.4, 121.8, 115.4, 115.3, 114.9, 102.3, 51.3, 51.1, 47.3, 41.9, 31.4, 29.1, 27.9, 22.3, 13.9. MS (ES+) m/z 445.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17]I)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1.N(CC)CC>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH3:17])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1
Reactant: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](CI)[C@H]1O
Agent: [Ni]
Solvent: CCNCC
Solvent: CO
Product: C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 31.1 %

Procedure:
To the solution of iodide 95 (85 mg, 0.16 mmol) in methanol (1.6 mL) was added Et2NH (0.03 mL, 0.31 mmol) and Raney nickel (20 mg). The reaction mixture was stirred 1 d under H2 (1 atm), filtered on Celite and evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford title compound 96 (21 mg, 31%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][CH2:3]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[CH3:25])[CH2:3]1
Reactant: CC1(C)CNC(=O)c2cc(C(F)(F)F)ccc21
Reactant: Cc1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CC(C)(C)c2ccc(C(F)(F)F)cc2C1=O
Yield: 5.5 %

Procedure:
Using analogous reaction conditions as described in Example 1, 4,4-dimethyl-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-20d: 200 mg, 0.8230 mmol) was reacted with 3-bromo-4-methyl-pyridine (91.9 mL, 0.8230 mmol), 1,4-dioxane (3 mL), copper iodide (15.6 mg, 0.0823 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (38.8 mL, 0.2469 mmol) and potassium phosphate (436.1 mg, 2.0575 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 15 mg of the product (5.44% yield).
Reaction SMILES: [NH2:1][C:2]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:20]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([S:36]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH:29]=[C:28]1B(O)O)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN1CCN(S(C2C=C3C(=CC=2)NC(B(O)O)=C3)(=O)=O)CC1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:28]2[N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:35]3[C:30]([CH:29]=2)=[CH:31][C:32]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)(=[O:37])=[O:38])=[CH:33][CH:34]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CN1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Reactant: Nc1c(-c2ccccc2)cc(Br)c2c1C(=O)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN1CCN(S(=O)(=O)c2ccc3[nH]c(B(O)O)cc3c2)CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2ccc3c(c2)cc(-c2cc(-c4ccccc4)c(N)c4c2C(=O)NC4=O)n3C(=O)OC(C)(C)C)CC1
Yield: 20.6 %

Procedure:
In a similar manner to Step 2 of Example 1, 3-amino-4-phenyl-6-bromophthalimide (70.0 mg, 0.221 mmol) was dissolved in acetonitrile (5.6 mL), and the solution was treated with a mixture (281 mg) of 1-(tert-butoxycarbonyl)-5-(4-methylpiperazin-1-ylsulfonyl)indol-2-boronic acid synthesized in a similar manner to the literature [Bioorganic & Medicinal Chemistry Letters, 2004, vol. 14, p. 351] and 5-(4-methylpiperazin-1-ylsulfonyl)-1H-indol-2-boronic acid, palladium acetate (4.0 mg, 0.018 mmol), tri(o-tolyl)phosphine (11 mg, 0.035 mmol) and triethylamine (0.308 mL, 2.21 mmol), followed by purification by preparative thin-layer chromatography (ethyl acetate/methanol=20/1) to obtain Compound 2 (21 mg, yield 19%) and 3-amino-4-phenyl-6-[1-(tert-butoxycarbonyl)-5-(4-methylpiperazin-1-ylsulfonyl)indol-2-yl]phthalimide (28 mg, yield 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH:23]1[C:27]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH3:19])[C:15]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([C:27]4[NH:26][N:25]=[N:24][N:23]=4)=[CH:29][CH:30]=3)=[O:17])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: CCC(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
212 mg (purity 60%, 0.4 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) (Example 3.1C) and 31 mg (0.19 mmol) of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 143 mg (77% of theory)