Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][O:20][CH2:19][CH2:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A solution of 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.0 g, 3.7 mmol) in N,N-dimethylformamide was added dropwise to a suspension of sodium hydride (0.19 g of a 60% dispersion in mineral oil, 4.8 mmol) in N,N-dimethylformamide (20 ml). The reaction was maintained for 2 hours followed by the dropwise addition of benzyl 3-bromopropyl ether (0.72 ml, 4.1 mmol). The reaction was stirred overnight at 100° C., quenched by pouring over ice, and extracted with ethyl acetate. The organic fractions were washed with water, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide 0.45 g of 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[C:9]([C:14]#[N:15])=[CH:10][NH:11]2)=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].C(Cl)Cl>[Cl:22][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:17][CH3:18])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Mixed 122 mg (0.50 mmol) 7-ethoxy-1,4-dihydro-6-methoxy-4-oxo-quinoline-3-carbonitrile and 2.0 ml methylene chloride under N2 and kept temperature near 25° C. Added 218 μl (2.5 mmol) oxalyl chloride and 10 μl (0.125 mmol) DMF. Stirred overnight, diluted with chloroform and stirred in saturated sodium bicarbonate until basic. Separated layers and dried organics with magnesium sulfate, stripped solvent and dried in vacuo, giving 117 mg of tan solid: mass spectrum (electrospray m/e): M+H=262.8, 264.8.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([NH2:19])=[C:13]([CH3:20])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:1])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccccc1
Yield: 80 %

Procedure:
By using 2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 80%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(N)c(C(=O)O)c1
Reaction time: 3.5 h
Yield: 99.5 %

Procedure:
To a solution of 5-isopropoxy-2-nitro-benzoic acid (946 mg, 4.2 mmol) in THF (15 mL) was added 5% Pd/C (95 mg) under a nitrogen atmosphere. A balloon filled with H2 was set up. The mixture was stirred for 3.5 h and filtered. The filtrate was dried to yield 816 mg of 5-isopropoxy-2-amino-benzoic acid.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][C:23]([OH:25])=O)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:55]([CH2:57][NH2:58])[OH:56]>C1COCC1.O.C([O-])(O)=O.[Na+]>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][C:23]([NH:58][CH2:57][CH2:55][OH:56])=[O:25])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCC(=O)NCCO
Reaction time: 3 h
Yield: 25.5 %

Procedure:
To a solution of 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)acetic acid (780 mg, 1.65 mmol) in THF (30 mL), HOBt (267 mg, 1.98 mmol) followed by EDC HCl (379 mg, 1.98 mmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (121 mg, 1.98 mmol) is added. Stirring is continued for 3 h. The mixture is diluted with water and sat. aq. NaHCO3 solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (202 mg) as a colourless oil; LC-MS: tR=1.07 min, [M+H]+=481.01; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.89 (s, 1H), 7.50 (d, J=0.5 Hz, 1H), 7.35 (t br, J=5.3 Hz, 1H), 7.30 (d, J=0.8 Hz, 1H), 4.39 (s, 2H), 4.02 (s, 3H), 3.87 (t, J=4.9 Hz, 2H), 3.63 (m, 2H), 3.51 (s, 2H), 3.20-3.29 (m, 1H), 2.73 (q, J=7.6 Hz, 2H), 2.38 (s, 3H), 2.06-2.15 (m, 2H), 1.84-1.95 (m, 4H), 1.70-1.80 (m, 2H), 1.33 (t, J=7.6 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]1[CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.[N:30]1([O:39][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON.Cl.CN1CCOCC1>CN(C=O)C>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]1[CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:30][OH:39])=[O:18]
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(CCc2ccccc2)C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)NO)N1C(=O)NC(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of the compound obtained in step e above (109 mg, 0.36 mmol) in DMF (1.8 mL) was added BOP (190 mg, 0.43 mmol) at 0° C. After stirring for 30 min, HONH2×HCl (50 mg, 11.38 mmol) and N-methylmorpholine (0.16 mL, 1.44 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between EtOAc and a saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc, dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (63 mg, 55% yield).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([S:9](Cl)(=[O:11])=[O:10])[CH2:5][CH2:4]1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][O:25][CH:26]2[CH2:31][CH2:30][N:29]([S:9]([N:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)(=[O:11])=[O:10])[CH2:28][CH2:27]2)=[O:23])=[CH:17][CH:16]=1
Reactant: O=C(NOC1CCNCC1)Nc1ccc(F)cc1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)N2CCC(ONC(=O)Nc3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
4-Methylpiperazine-1-sulfonyl chloride hydrochloride (227 mg, 0.966 mmol) was added at room temperature to a solution of 1-(4-fluorophenyl)-3-(piperidin-4-yloxy)urea hydrochloride (140 mg, 0.483 mmol) and K2CO3 (200 mg, 1.45 mmol) in H2O-dioxane (1:1, 4 ml), and the whole was stirred at room temperature for 18 hours. The reaction was quenched with K2CO3 (200 mg) in H2O (10 ml), extracted with ethyl acetate (20 ml×3). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (chloroform/methanol: 90/10) to give 1-(4-fluorophenyl)-3-(1-(4-methylpiperazin-1-ylsulfonyl)piperidin-4-yloxy)urea (139 mg, 69%) as pale yellow amorphous: LCMS: 416 [M+1]+. 1H NMR (DMSO-d6) δ: 1.72 (m, 2H), 1.93 (m, 2H), 2.19 (s, 3H), 2.35 (m, 4H), 3.01-3.13 (m, 6H), 3.45 (m, 2H), 3.85 (m, 1H), 7.11 (m, 2H), 7.55 (m, 2H), 8.68 (s, 1H), 9.45 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]1)=[O:18])=[CH:10][CH:9]=2)#[CH:4].[CH2:28](Br)[C:29]#[CH:30].O>C1COCC1>[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]1([CH2:24][O:25][CH2:30][C:29]#[CH:28])[CH2:23][CH2:22][CH2:21]1)=[O:18])=[CH:10][CH:9]=2)#[CH:4]
Reactant: C#CCBr
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(CO)CCC3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOCC1(NC(=O)C(Oc2ccc3ncc(C#C)cc3c2)SC)CCC1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
NaH (172 mg, 60% in oil) was added to a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (850 mg) in THF (50 ml), at room temperature, under nitrogen atmosphere. The mixture was stirred until gas evolution ceased (30 min). Propargyl bromide (638 mg, 80% toluene solution) was added and the mixture was stirred at 40° C. during 3 hours, and then after cooling to room temperature poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/CH2Cl2, 1/1/1) to give 2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-N-(1-prop-2-ynyloxymethyl-cyclobutyl)-acet-amide (146 mg) as slightly brown oil. 1H NMR (CDCl3) δ ppm: 8.82 (1H, d); 8.18 (1H, d); 8.03 (1H, d); 7.44 (1H, dd); 7.21 (1H, d); 6.88 (1H, br s); 5.62 (1H, s); 4.14 (2H, s); 3.84-3.74 (2H, dd, AB system); 3.28 (1H, s); 2.49-2.13 (4H, m); 2.42 (1H, s); 2.19 (3H, s); 2.01-1.79 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:10][C@H:11]([C@H:28]([OH:30])[CH3:29])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@H:28]([OH:30])[CH3:29])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(S(C)(=O)=O)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(S(C)(=O)=O)cc3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 26 %

Procedure:
To a 250 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)-4-(methylsulphonyl)benzohydrazide (855 mg, 1.8 mmol) followed by a addition of anhydrous THF (200 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (350 mg, 1.8 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading, 2.51 g, 5.5 mmol). This mixture was allowed to stir at room temperature for 6.5 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a red solid. This was purified via silica gel chromatography eluted with 70% EtOAc/hexanes to yield product as a white solid (209 mg, 25%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.25 (AA′XX′, J=8.4 Hz, 2H), 8.13 (AA′XX′, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.90 (d, J=9.0 Hz, 1H), 5.11 (dd, J=5.6, 8.9 Hz, 1H), 4.70 (d, J=6.0 Hz, 1H), 4.55 (m, 1H), 3.19 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[Br:14]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:14])=[CH:4][C:3]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(Br)c(Cl)cc1Cl

Procedure:
500 parts of 2,4-dichlorotoluene (b.p.=198° to 200° C.) and 10 parts of anhydrous aluminum chloride were charged into a 1-liter four-necked flask provided with a reflux condenser, a thermometer, a stirrer and a dropping funnel. 397 parts of bromine was added dropwisely at 30° to 40° C. over a period of 5 hours. The reaction liquid was washed with warm water followed by separating the water layer, and then the oil layer was cooled. The separated crystals were filtered off, recrystallized from methanol to obtain 295 parts of 2,4-dichloro-5-bromotoluene having a melting point of 82.5° to 84.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]([NH:16][C@H:17]([C:21]([NH:23]C(OC(C)(C)C)=O)=[O:22])[CH2:18][S:19][CH3:20])[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)=[O:4].[ClH:31]>C(OCC)(=O)C>[ClH:31].[CH3:1][O:2][C:3]([CH2:5][N:6]([NH:16][C@H:17]([C:21]([NH2:23])=[O:22])[CH2:18][S:19][CH3:20])[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)=[O:4]
Reactant: COC(=O)CN(N[C@@H](CSC)C(=O)NC(=O)OC(C)(C)C)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CN(N[C@@H](CSC)C(N)=O)c1ccc2c(c1)OCO2
Yield: 83 %

Procedure:
After 4.67 g (11 mmol) of (N-methoxycarbonylmethyl-1,3-benzodioxol-5-ylamino)-N-t-butoxycarbonyl-S-methyl-L-cysteinamide were dissolved in 100 ml of ethyl acetate, an excess of hydrochloric acid was ebulated. A precipitate so formed was collected by filtration, washed with ether and then dried under reduced pressure, whereby 3.3 g of (N-methoxycarbonylmethyl-1,3-benzodioxol-5-ylamino)-S-methyl-L-cysteinamide hydrochloride were obtained (yield: 83%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])C.Br[O-].[Na+].S(=O)(O)[O-:23].[Na+].Cl>O1CCOCC1>[F:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:23])=[CH:5][CH:6]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: O=S([O-])O
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 50 g (0.20 mol) of the above 4-acetyl 3'-fluoro-4'-methoxy biphenyl in 2 l of dioxane was added 1000 ml of an aqueous solution of sodium hypobromite (prepared from 338 g of sodium hydroxide and 486 g of bromine) over about 4 hours while cooling to not higher than 10° C., which was stirred at 25°-30° C. for about 3 hours. Thereafter, an aqueous saturated solution of sodium bisulfite was added to decompose the excessive amount of sodium hypobromite and then added with a concentrated hydrochloric acid to adjust pH to approximately 1. After the leaving over two nights, the precipitated crystal was filtered and recrystallized with ethanol and further with acetic acid to obtain 43 g (yield: 85%) of 3'-fluoro-4'-methoxybiphenyl-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH2:29]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 33.4 %

Procedure:
In a 100-ml round-bottomed flask were placed 2,4-dichlorobenzylamine (3.5 g (20 mmol)), triethylamine (4.0 g (40 mmol)), and chloroform (10 ml) under nitrogen. While stirring, laurylbromide (4.9 g (20 mmol)) in chloroform (5 ml) was added dropwise at 50°-60° C. The mixture was stirred for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The resultant concentrate was dissolved in ethyl acetate, washed with water, and purified via silica gel column chromatography (chloroform:methanol=10:1), thereby obtaining 2.3 g of N-lauryl-2,4-dichlorobenzylamine as pale yellow crystals (yield: 34%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH2:16])=[C:7]([C:14]#[CH:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:16][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][C:7]=1[C:14]#[CH:15]
Reactant: C#Cc1cc2cn[nH]c2c(C(=O)OC)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C#Cc1cc2cn[nH]c2c(C(=O)O)c1N
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 200 mg (0.93 mmol) of 6-amino-5-ethynyl-1H-indazole-7-carboxylic acid methyl ester in 4.2 mL of dioxane and 0.2 mL of methanol is added 2.3 mL (2.3 mmol) of a 1N aqueous solution of NaOH. The mixture is stirred for 5 hours at 50° C. The solvents are evaporated and water is added to the residue. The product is precipitated at pH 4 by addition of 1N aqueous HCl, filtrated, washed with a minimum of water and dried by azeotropic distillation with toluene. The yellowish solid obtained is used directly in the next step; LC/MS: 202/203 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](/[CH:13]=C/COC)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[O:18]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:18])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC/C=C/c1cc(C(=O)OC)cc(Br)c1C
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C)c(C=O)c1
Temperature: 25 °C

Procedure:
To a dichloromethane (0.16 M) solution of methyl 3-bromo-5-[(1E)-3-methoxy-1-propen-1-yl]-4-methylbenzoate (1 eq., Amine 88, Step 1) was bubbled at −78° C. with freshly generated ozone until a persistent blue color was observed. The reaction vessel was then thoroughly purged with nitrogen before triphenylphosphine (1.1 eq.) was added. The resulting mixture was slowly warmed to RT over 6 h. The volatiles were then removed in vacuo and the resulting residue was suspended in a 1:1 (v/v) mixture of hexanes and ether. The insolubles were removed via filtration through a pad of silica gel. Concentration of the filtrate thus obtained in vacuo afforded a white solid. Further purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:10][C:11]=2[C:12](=O)/[CH:13]=[CH:14]/N(C)C)=[CH:4][CH:3]=1.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].[O-]CC.[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][N:28]=[C:29]([NH2:31])[N:30]=2)=[CH:25][CH:26]=1
Reactant: CN(C)/C=C/C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1nccc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)n1
Yield: 62 %

Procedure:
To a solution of (E)-1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (93.0 mg, 0.242 mmol) in isopropyl alcohol (1.0 mL) was added guanidine hydrochloride (34.7 mg, 0.363 mmol) and sodium ethoxide (65.4 mg, 1.21 mmol) and the resulting mixture was heated to reflux for 3 days. The reaction was cooled and concentrated in vacuo. The residue was slurried in DCM (10 mL) and water (10 mL). The undissolved solids were filtered. This material was purified by preparative reverse phase chromatography to give 57 mg (62% yield) of the title compound as a white solid. LC/MS (FA) ES+ 380, 382. 1H NMR (300 MHz, DMSO-d6) δ 8.73-8.71 (m, 2H), 8.31 (d, 1H, J=5.1 Hz), 7.88-7.86 (m, 2H), 7.36-7.30 (m, 4H), 6.86 (bs, 2H), 6.84 (d, 1H, J=5.1 Hz), 4.56 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[N:7]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]1[C:11]([NH:12][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: COc1ccc(N)c(NCC(OC)OC)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(OC)nc1NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N2-[2,2-bis(methyloxy)ethyl]-6-(methyloxy)-2,3-pyridinediamine (2.2 g, 10 mmol), ethyl bromoacetate (1.1 mL, 1.65 g, 10 mmol) and potassium carbonate (2.1 g, 20 mmol) in acetonitrile (50 mL) and DMF (5 mL) was stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic extract was concentrated and added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording product (2.5 g, 82%).
Reaction SMILES: [ClH:1].[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1.C=O.[C:23](O)(=O)C.C([BH3-])#N.[Na+]>CO.[OH-].[Na+].O>[ClH:1].[CH3:23][N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][N:3]2[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(N2C[C@@H]3C[C@H]2CN3)c2ccccc12
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc(C#N)c2ccccc12
Reaction time: 0.08 h

Procedure:
165RL09 (26.4 mg, 0.106 mmol) was dissolved in methanol (5 mL) and formaldehyde (37% in water, 16 μL, 0.21 mmol) was added. The mixture was acidified by adding acetic acid (10 μL). After 5 min of shaking, sodium cyanoborohydride (46.6 mg, 0.741 mmol) was added and the mixture was allowed to react for 2 hours. The mixture was hydrolyzed by adding 5 drops of sodium hydroxide (2M) followed by water (10 mL) and the mixture extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness. The product (23 mg, 83%) needed no further purification and was converted to the corresponding hydrochloride salt as described above.