Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:22].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(C(O)CN(CCO)C(=O)OC(C)(C)C)cnc1Br
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (2.57 g) and triethylamine (1.51 ml) in THF (30 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (546 •1). The reaction mixture was then stirred at room temperature for 15 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (10 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (5.62 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 10 min and then poured into EtOAc and washed sequentially with water and with saturated brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.7 g, 73% over 3 steps) as a colourless oil. MS (ISP): 359.0 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [CH:1]1([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[CH3:15])=[CH:9][C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.CCN(CC)CC.[BH3-]C#N.[Na+]>O1CCOCC1.O=[Mn]=O>[CH:1]1([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:32]4[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]4)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[CH3:15])=[CH:9][C:8]=2[C:28]([F:29])([F:30])[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CO
Reactant: O=C(O)C1CNC1
Agent: O=[Mn]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CN1CC(C(=O)O)C1
Temperature: 50 °C

Procedure:
To a suspension of MnO2 (10 eq) in dioxane is added 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with azetidine-3-carboxylic acid (2 eq) and Et3N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes. After cooling to room temperature, NaBH3CN (3 eq) is added in portions. Purification by preparative LCMS results in 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid; 1H NMR (400 MHz, CD3OD) δ 1.24 (t, 3H), 1.30-1.60 (m, 5H), 1.74-1.92 (m, 5H), 2.28 (s, 3H), 2.79 (q, 2H), 2.92 (m, 1H), 3.68 (m, 1H), 4.32 (m, 4H), 4.51 (s, 2H) 5.22 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (m, 5H). MS: (ES+): 517.3 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:29]2[CH2:30][CH2:31][N:27]([CH3:26])[C:28]2=[O:32])[CH:7]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)nc1C
Yield: 12.8 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (846 mg) described in Preparation Example 257 and 1-methylimidazolidin-2-one (300 mg) and by the reaction and treatment in the same manner as in Preparation Example 241, the title compound (113 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH:13]1[CH:18]2[CH:14]1[CH2:15][N:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17]2)[CH2:8][CH2:9][CH2:10][CH2:11]Br)(C)(C)[CH3:2].BrCCCCl.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH:41]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:42][C:43]([OH:45])=[O:44].N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH2:19]([N:16]1[CH2:15][CH:14]2[CH:18]([CH:13]2[N:7]([C:6]([O:5][CH2:1][CH3:2])=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][O:44][C:43](=[O:45])[CH2:42][CH:41]([C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[O:33][CH3:32])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:17]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(CCCCBr)C1C2CN(Cc3ccccc3)CC21
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Agent: ClCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)N(CCCCOC(=O)CC(c1ccccc1)c1cc(C)ccc1OC)C1C2CN(Cc3ccccc3)CC21

Procedure:
The compound, 3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-(4-bromobutyl)-carbamic acid t-butyl ester, 211.5 mg, 0.5 mmole, 1 eq (prepared by reacting boc-protected 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett, 1996, 1100, with 1-bromo-3-chloropropane) was dissolved in xylene (15 ml). To the reaction mixture, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (203 mg, 0.75 mmole, 1.5 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.75 mmole, 1.5 eq) were added. The resulting reaction mixture was refluxed for 2 hrs. Xylene was removed under reduced pressure and the residue was purified by column chromatography by using ethyl acetate in hexane solvent system to yield the compound, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid 4-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-ethoxy carbonylamino]butyl ester.
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.[F:63]C1C=CC(C(Cl)=O)=CC=1>ClCCl>[F:63][C:32]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[N:13][CH:12]=2)[CH3:10])=[O:7])=[CH:4][CH:33]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(F)cc3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.30 g, 1.0 mmol), triethylamine (0.28 mL, 2.0 mmol) and 4-fluorobenzoyl chloride (0.16 g, 1.0 mmol) in dichloromethane (10 mL) gave 4-fluoro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.32 g) as a white solid. MS m/z 428 (M+1).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine-1-yl]-ethyl}-methyl-amine (0.18 g, 0.49 mmole) and triethylamine (0.14 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylic acid chloride (0.10 g, 0.59 mmole) in 1 mL dichloromethane was added and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated and the organics washed with water (50 mL), brine (25 mL) and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:4 EtOAc-hexane) gave 0.13 g (55% yield) of the titled compound. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid. m.p. 146-151° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:12]=1)([CH3:10])[CH3:9]>ClCCl>[CH:8]([C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccn(CC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccn(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
Trifluoroacetic acid (1.20 mL, 15.70 mmol) was added to a solution of tert-butyl 2-(3-isopropyl-pyrrol-1-yl)acetate (350 mg, 1.57 mmol) in dichloromethane at 0° C. and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo and the residue was basified with saturated sodium bicarbonate solution. The solution was washed with diethyl ether and the alkaline solution was then acidified with concentrated aqueous HCl and extracted with diethyl ether. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 69%) as a semi-solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>CN(C)C=O>[O:12]=[C:10]([CH3:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7][CH:6]=1
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(CCC(C)=O)cc1

Procedure:
The hapten [10-O-(carboxypropyl)]ractopamine ether(Hapten A—derivatised at position 10) was prepared in three steps according to FIG. 3 of the accompanying drawings, from 4-(4-hydroxyphenyl)-2-butanone, 2. The reaction of 4-(4-hydroxyphenyl)-2-butanone, 2 with ethyl 4-bromobutyrate in dimethylformamide (DMF) in the presence of sodium hydride (NaH), gives ethyl 4-[4-(3-oxobutyl)phenoxy]butanoate 3. The ketoester, 3, obtained was reacted with octopamine hydrochloride, 4, in methanol in the presence of triethylamine (TEA) and sodium cyanoborohydride (Na BH3CN) to give 10-O-[3-(ethoxycarbonyl)propyl]ractopamine ether 5, in moderate yields. The hapten A was obtained after saponification of the ester, 5, with sodium hydroxide (NaOH) (2N) in methanol.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si](C(C)(C)C)(C)C)=[N+]=[N-].CC1CC=CCC=1.[ClH:40].O1CCOCC1>C(O)C.[Pd]>[ClH:40].[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[OH:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of (R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one (4.50 g, 10.0 mmol) in ethanol (50 mL) was added 10% palladium on charcoal (4.50 g) followed by 1-methyl-1,4-cyclohexadiene (11.0 mL, 97.9 mmol). The reaction was warmed to 60° C. and then stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool and filtered through a pad of celite. The filtercake was washed with further ethanol and the filtrate was evaporated at reduced pressure. The residue was evaporated from iso-propanol (×2) and dissolved in iso-propanol (30 mL). HCl-dioxane (4M, 50 mL, 200 mmol) was added and the reaction mixture stirred at RT for 18 hours. The resultant suspension was filtered, the filtercake washed with ether and the solid dried under vacuum in the presence of P2O5 to afford the title compound (1.65 g, 62%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[O:9]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH2:21][NH:22][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CCNCc3cccnc3)cc2)cc1
Temperature: 5 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
A solution of pyridine-3-carboxaldehyde (322 mg, 3.0 mmol) and 4-phenoxyphenethylamine (747 mg, 3.5 mmol) in reagent grade methanol (5 mL) under nitrogen was refluxed for 2 h, then cooled to 5° C. (ice bath), and diluted with more methanol (5 mL). Sodium borohydride (0.23 g, 6 mmol) was added, and the mixture was slowly allowed to reach room temperature and stirred at room temperature overnight (18 h). The mixture was concentrated in vacuo, taken up in dichloromethane, and filtered. The filtrate was concentrated in vacuo and chromatographed on silica gel (eluted with 7% methanol/dichloromethane) to afford N-((4-phenoxy)phenylethyl)pyridine-3-methylamine (863 mg, 94%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22](O)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1.[CH3:25][O:26][CH2:27]Cl>C(N(CC)CC)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1
Reactant: COCCl
Reactant: Oc1ccc2nc(-c3ccc(I)cc3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 0.76 mmol) was added to a DMF (2 mL) solution of 5 (225 mg, 0.64 mmol), cooled in an ice bath. After stirring at 0° C. for 1 h, chloromethyl methyl ether (100 μL, 1.33 mmol) and triethylamine (0.2 mL) were added. The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with pH 7 buffer solution (10 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash chromatography on silica gel (CH2Cl2), to give 2-(4-iodophenyl)-6-(methoxymethyl)-1,3-benzothiazole (6) (237 mg, 93.7%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26]([N:33]([CH3:41])[C@@H:34]([C:38]([OH:40])=O)[CH:35]([CH3:37])[CH3:36])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1.ClCCl>[C:29]([O:28][C:26](=[O:27])[N:33]([CH3:41])[CH:34]([C:38](=[O:40])[N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[CH:35]([CH3:36])[CH3:37])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A mixture of compound 7B (240 mg, 0.702 mmol), Boc-N-methyl-D-valine (176 mg, 0.762 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (208 mg, 1.085 mmol), 1-hydroxybenzotriazole (146 mg, 1.085 mmol), dichloromethane (5 mL) and THF (2.5 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column, which was eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (282 mg, 72% yield).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C1(O)C=CC=CC=1.O>[CH3:17][C:18]1[CH:19]=[C:20]([N:21]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(N)c1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: Oc1ccccc1
Solvent: O
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1cccc(C)c1
Temperature: 190 °C
Yield: 75.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol in a pressure tube and 3-methylaniline (268 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 230 mg of desired compound as solid in 76% of yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1)#[CH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C)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.[Cu]I>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:18])=[N:6][CH:7]=2)[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)cc(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 5-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (573 mg, 3.0 mmol), 1-ethynyl-3,5-dimethoxybenzene (483 mg, 3.0 mmol), triphenylphosphine (157 mg, 0.60 mmol), bis(triphenylphosphine)palladium(II) chloride (210 mg, 0.30 mmol), copper(I) iodide (57 mg, 0.30 mmol) and diethylamine (1.50 ml, 15.0 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen three times, and then stirred at 80° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was cooled to RT, quenched with water (20 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=4:1) to afford the title compound as a yellow solid (460 mg, 39%). MS (ES+) C21H18N4O4 requires: 390. found: 391 [M+H]+.
Reaction SMILES: NC(C)/[CH:3]=[CH:4]/[C:5]([NH:7][C@@H:8]1[CH2:13][C@H:12](C)[C@H:11](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)C2)[O:10][C@@H:9]1C)=O.NC(C)/C=C\C(N[C@@H]1C[C@H](C)[C@H](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)C2)O[C@@H]1C)=[O:40].[P:69]([O-:73])([O-:72])([O-:71])=[O:70].[Na+].[Na+].[Na+].C(N)(C)C>CS(C)=O.P([O-])([O-])([O-])=O>[CH3:9][C:8]1[N:7]=[CH:5][C:4]([CH2:3][O:70][P:69]([OH:73])([OH:72])=[O:71])=[C:12]([CH:11]=[O:10])[C:13]=1[OH:40].[P:69]([O-:73])([O-:72])([O-:71])=[O:70]
Reactant: CC(/C=C/[C@@H]1C[C@]2(CO2)C[C@@H](CC(N)=O)O1)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C/C(C)N)C[C@@H]1C
Reactant: CC(/C=C/[C@@H]1C[C@]2(CO2)C[C@@H](CC(N)=O)O1)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\C(C)N)C[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)N
Solvent: CS(C)=O
Product: Cc1ncc(COP(=O)(O)O)c(C=O)c1O

Procedure:
Synthesis of (2E)-4-amino-N-[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3S,5S,7S)-7-(2-amino-2-oxoethyl)-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]pent-2-enamide (#B271) and (2Z)-4-amino-N-[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3S,5S,7S)-7-(2-amino-2-oxoethyl)-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]pent-2-enamide (#B272): To 100 mM sodium phosphate buffer pH 7.4 (3.57 ml) were added #B129 (7 mg, in 0.23 ml DMSO, 1 eq.), isopropylamine (1.475 ml of a 1 M solution made in phosphate buffer pH 3, giving a solution of pH ˜7, 100 eq.), pyridoxal phosphate (0.295 ml of a 50 mM solution in phosphate buffer pH 7.4, 1 eq.), and ATA-P2-B01 enzyme preparation (33 mg, in 0.33 ml phosphate buffer pH 7.4, Codexis, lot #D11134, R-selective for acetophenone). After incubation at 30° C., 200 rpm for 19 hours, pH was adjusted to ˜12 with sodium hydroxide and the reaction was extracted seven times with equal volume of ethylacetate. The solvent was evaporated under reduced pressure, the residue resuspended in 0.25 ml acetonitrile/water 1:1, filtered and purified by reverse phase chromatography in a total of 10 runs (Method I). The fractions with retention time of 10 and 13 min were collected and neutralized with ammonium hydroxide before freeze-drying to afford #B271 and #B272, respectively, as white solids.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:24][CH2:22][CH3:23])[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: CCN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1cc(Cl)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
A suspension of 5A (80 mg, 0.245 mmol), ethanamine (0.6 mL, 1.200 mmol, 2 M/THF) and DIEA (0.086 mL, 0.491 mmol) in NMP (0.7 mL) was heated at 80° C. for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration and washed with a small amount of DCM to give 6-chloro-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a yellow solid 62.8 mg. HPLC Rt=2.517 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=335.