Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)[N:4]2[C@H]1C(O)=O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:49][C@@H:50]2[O:55][C@@H:54]([CH2:56]O)[C@H:53](O)[C@@H:52](O)[C@@H:51]2[NH:60]C)[C@@]1(O)C=O.CCCCO.CC(O)CO.C(O)CO.C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[Na+]>OCC(CO)O>[NH2:60][C@H:51]([C:50]([OH:55])=[O:49])[CH2:52][CH2:53][CH2:54][CH2:56][NH2:4]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CC(O)CO
Solvent: CCCCO
Solvent: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
A glycerol stock of the strain in which fadIJ operon was amplified, the strain being obtained in of Example 9, was thawed. 100 μL of each was evenly spread on an LB agar medium plate containing 50 mg/L ampicillin and 25 mg/L streptomycin and incubated at 37° C. for 24 hours. About ¼ volume of bacterial cells on the plate was suspended in 1.0 mL of saline and turbidity thereof at a wavelength of 600 nm was measured by Spectrophotometer U-2000 (Hitachi). The obtained suspension containing the bacteria was inoculated into 40 mL of fermentation medium described below containing 50 mg/L ampicillin and 25 mg/L streptomycin in a 500 mL-Erlenmeyer flask equipped with baffles such that the turbidity thereof at a wavelength of 600 nm was 0.25; and cultured using a rotary shaking culture apparatus at a stirring rate of 200 rpm at 37° C. for 48 hours. As a carbon source in a main culture, sodium oleate added with polyoxyethylene sorbitan monooleic acid ester (Tween 80: manufactured by NACALAI TESQUE, INC.) as an emulsification promoter to a final concentration of 0.5% (w/v) was used. As for a total amount of carbon sources, sodium oleate was 10 g/L. The medium composition used for the culture is shown below.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Yield: 87.8 %

Procedure:
A solution of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (2.52 g, 11.0 mmol) and piperazine (2.83 g, 32.8 mmol) in acetonitrile (30 mL) was heated to refluxed for 2 hours. The solvent was removed by evaporation, the residue was dissolved in water (50 ml) and extracted with dichloromethane (3×100 mL). The organic extract was dried over anhydrous Na2SO4 and then evaporated. The residue was passed through a pad of silica gel and concentrated to give 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (2.68 g, 88% yield). MS (ES+) m/z 278 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:23]COC(C)=O.O>CO>[C:1]1([N:7]2[C:11]([C:12]([O:14][CH3:23])=[O:13])=[CH:10][C:9]([C:15]([F:17])([F:18])[F:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 0 °C

Procedure:
Intermediate 7 (1.55 g, 6.0 mmol) was dissolved in MeOH (15 ml), cooled to 0° C. and thionyl chloride (1.3 ml, 18.2 mmol) was added. Reaction mixture was heated to 60° C. for overnight. Work up (AcOEt:H2O) followed by evaporation on high vacuum obtained the title compound as an yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.51-7.47 (m, 3H), 7.46-7.41 (m, 2H), 7.50 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[CH2:22][CH2:23]I>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][N:8]2[CH2:23][CH2:22][C:21]([F:26])([F:25])[C:20]([F:28])([F:27])[F:19])=[CH:4][CH:3]=1
Reactant: N#Cc1n[nH]c2cc(Cl)ccc12
Reactant: FC(F)(F)C(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
An acetonitrile solution (450 mL) containing the intermediate from Step C (30 g, 169 mmol), potassium carbonate (116.6 g, 844 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (97.2 g, 354.7 mmol) was refluxed for 36 hours. The solution was cooled to room temperature and partitioned between EtOAc and water. The organic phase was concentrated and the crude material was filtered through a plug of silica gel using 10% EtOAc/heptanes as the eluent. The isolated material was subsequently recrystallized from heptanes to give the indicated product. 1H NMR (400 MHz, CH3 CN-d3): δ 7.87-7.80 (m, 2H); 7.40 (dd, J=8.7, 1.7 Hz, 1H); 4.77 (t, J=7.0 Hz, 2H); 2.95-2.78 (m, 2H). m/z=324.1 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1F
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2ccccc2F)c(-c2ccccc2)n1
Yield: 9.8 %

Procedure:
6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (44 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 2-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:24][CH2:25]1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Product: COc1ccccc1N1CCN(CCCCNc2cc(Cl)ccc2[N+](=O)[O-])CC1

Procedure:
The compound was prepared according to the method described in Farmaco Ed. Sci. 36, 359 (1981) from 2,4-dichloronitrobenzene and 4-(2-methoxyphenyl)-1-piperazinbutanamine. M.p. 227°-229° C. as hydrochloride salt.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[H-].[Na+].I[CH3:29]>O1CCCC1.O>[CH3:29][N:22]([C:20]1[CH:19]=[N:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:12][CH:13]=2)[CH:21]=1)[C:23](=[O:25])[CH3:24]
Reactant: CI
Reactant: CC(=O)Nc1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a solution of N-[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]acetamide obtained in Example 37 (0.34 g) in tetrahydrofuran (3.5 mL), sodium hydride (55% in mineral oil, 0.048 g) was added and iodomethane (0.225 g) was then added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: ethyl acetate:hexane=1:1→ethyl acetate), and the resulting crystal was washed with diisopropyl ether to give the titled compound (0.187 g) as a white solid.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=2[Cl:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]3[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:35]=3[CH:34]=2)=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]3[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:35]=3[C:34]=2[C:15]([C:14]2[CH:18]=[CH:19][C:11]([O:10][CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:12]([Cl:20])[CH:13]=2)=[O:17])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(Cl)c1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.6 g(8.12 mmol) of 4-[2-(1-piperidinyl)ethoxy]-3-chlorobenzoic acid hydrochloride was dissolved in 25 mL of dichloromethane and 50 mL of SOCl2 with three drops of DMF. The reaction was reluxed for sixteen hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, then re-dissolved in 50 mL of dichloromethane. 2.2 g (8.12 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene was added to the solution and cooled to 0° C. 7.6 g (56.8 mmol) of AlCl3 was added in three portions to the reaction mixture and allowed to proceed for 1.5 hours. The reaction was quenched by pouring into ice. The organic layer was separated and washed with Na2CO3 solution and with water. The organic layer was dried by filtration through Na2SO4 and evaporated to dryness. The crude material was chromatographed on a silica gel column (HPLC) with a linear gradient beginning with CHCl3 and ending with MeOH-CHCl3 (1:9). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 1.3 g of the title compound as a yellow amorphous foam. PMR: Consistent with the proposed structure
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH3:12].C(O)(=O)C>CCO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][CH3:12]
Reactant: CNc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CNc1c(N)cccc1Cl
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
2-Chloro-N-methyl-6-nitrobenzenamine (1.5 g, 8.0 mmol) was dissolved in a mixture of EtOH (15 mL) and H2O (15 ml). Iron powder (2.2 g, 40 mmol) was added followed by Acetic acid (0.55 mL, 9.6 mmol). The reaction was monitored by TLC, after 30 min, the reaction was completed. The reaction mixture was filtered over celite pad and the filtrate was neutralized by saturated NaHCO3 (10 mL). The product was extracted by EtOAc (2*10 mL), the organic layer was washed with brine (10 mL), dried over MgSO4 and concentrated to dryness to afford 920 mg of 6-chloro-N1-methylbenzene-1,2-diamine (Yield: 73%) as dark brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[C:57]([C:59]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)#[N:58]>ClCCl.CN(C)C=O>[C:57]([C:59]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:60][CH2:61][N:62]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:63][CH2:64]1)#[N:58]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Reaction time: 16 h
Yield: 16.6 %

Procedure:
To 300 mg (0.90 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy-phenyl)propanoic acid dissolved in 3.5 mL of dichloromethane and 1.5 mL of dimethylformamide are added 0.46 mL (2.7 mmol) of diisopropylethylamine, 318 mg (0.99 mmol) of TBTU and 220 mg (0.99 mmol) of 4-cyano-4-phenylpiperidine hydrochloride. After 16 hours, the solution is washed with saturated sodium hydrogen carbonate solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by filtration on a pad of silica (eluent: 7/3 dichloromethane/methanol). 75 mg of 1-[2-(4-cyano-4-phenylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea in the form of a white powder are obtained in a yield of 17%.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)c1ccccc1
Yield: 78 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 78-80% yield.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46]([O:48][C:49](=[O:70])[C@H:50]([O:52][C:53]1[CH:58]=[C:57](Cl)[N:56]=[C:55]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:54]=1)[CH3:51])[CH3:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:46]([O:48][C:49](=[O:70])[C@H:50]([O:52][C:53]1[CH:58]=[C:57]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:56]=[C:55]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:54]=1)[CH3:51])[CH3:47]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of methanesulfonamide (93 mg), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (52 mg), cesium carbonate (0.38 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30 g) and dioxane (10 mL). Purification was by column chromatography on silica using EtOAc/isohexane (1:1) as eluent to give the subtitle compound as an oil. Yield: 0.28 g
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[O:32][CH2:31][CH2:30][O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([Br:1])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(Br)c1
Reactant: BrCCCCCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of benzyl 3-bromo-5-hydroxybenzoate (2.85 g, 9.22 mmol) in dimethyl formamide (50 mL), was added 2-(8-bromooctyl)-1,3-dioxolane (2.44 g, 9.21 mmol) and potassium carbonate (1.91 g, 13.8 mmol), and the mixture stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-7% ethyl acetate in iso-hexane to afford the title compound (2.94 g, 65%).
Reaction SMILES: [C:1](=O)([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[O:2]C1C=CC=CC=1.[NH2:21][NH2:22]>CO>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:2])[NH:21][NH2:22]
Reactant: CC1(C)CC(OC(=O)Oc2ccccc2)CC(C)(C)N1
Reactant: NN
Solvent: CO
Product: CC1(C)CC(OC(=O)NN)CC(C)(C)N1
Reaction time: 3 h

Procedure:
Into a 300 ml 3-neck flask were added 16.9 grams (0,061 mole) of phenyl 2,2,6,6-tetramethyl-4-piperidinyl carbonate and 100 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 3.4 grams (0.067 mole) of 64% aqueous hydrazine. The hydrazine was added slowly to the stirring methanol solution at room temperature. There was a slight exotherm. The reaction mixture was stirred for 3 hours and then allowed to stand overnight (i.e. for 20 hours) at room temperature. The next day, the methanol was stripped off on a rotating evaporator and the liquid residue dissolved in 150 ml of MtBE and washed with 50 ml of 10% NaOH which was saturated with salt. The MtBE solution was dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue, a very viscous liquid, was slurried in 20 ml of hexane until a solid formed. The solid was filtered off and air dried. The product weighed 6.4 grams (49% crude yield), had a melting point of 93°-94° C. and gas chromatography indicated it was about 95% pure. The infrared scan contained a strong carbonyl peak at 1710 cm-1 and a moderate carbonyl peak at 1625 cm-1. An additional 5.26 grams of crude product was recovered by extracting the aqueous wash with methylene chloride and stripping off the solvent.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@H:36]([CH2:38][OH:39])[CH2:35][O:34]1.[CH3:41][C:42]1([CH3:49])[O:46][C@@H:45]([CH2:47]O)[CH2:44][O:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][OH:39])[CH2:35][O:34]1.[CH3:41][C:42]1([CH3:49])[O:46][C@@H:45]([CH2:47][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:44][O:43]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 4 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:23][O:24]CC1C=CC=CC=1)[CH2:9][O:10][CH2:11][C:12](=O)[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1)(C)(C)C>Cl.C(OCC)(=O)C>[F:21][C:15]1[CH:14]=[C:13]([C@H:12]2[NH:7][C@@H:8]([CH2:23][OH:24])[CH2:9][O:10][CH2:11]2)[CH:18]=[C:17]([F:19])[C:16]=1[F:20]
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
{(S)-1-benzyloxymethyl-2-[2-oxo-2-(3,4,5-trifluorophenyl)ethoxy]ethyl}carbamic acid t-butyl ester (82.6 g) was diluted with 4 N hydrochloric acid-ethyl acetate solution (500 mL), and the resultant was stirred at room temperature for 12 hours. The solvent was removed under a vacuum, and the resultant was dissolved in methanol (500 mL). 10% palladium on carbon (8.5 g, 50% water content) was added, and under a hydrogen atmosphere, stirring was continued for 22 hours. The catalyst was filtered off on celite, and the filtrate was concentrated under a vacuum. The residue was diluted with methanol (500 mL), and 20% palladium hydroxide on carbon (8 g, 50% water content) was added, and under a hydrogen atmosphere, stirring was continued for 4 hours. The catalyst was filtered off on celite, and the solvent was removed under a vacuum. Ethyl acetate (600 mL) and 1 N sodium hydroxide solution (250 mL) was added, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was suspended in ether (80 mL) and the resultant was filtered, and the title compound (22.34 g) was obtained. The physical property values are as follows.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:31][C@H:32]1[C@@H:36]([CH2:37][CH3:38])[CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:33]1)(=[O:3])[NH2:2].O.NN.C1COCC1>CCO>[NH2:20][CH2:19][C:16]1[N:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:6]3[C:5]([NH:31][C@H:32]4[C@@H:36]([CH2:37][CH3:38])[CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[O:40])[CH2:33]4)=[C:4]([C:1](=[O:3])[NH2:2])[CH:9]=[N:8][N:7]3[CH:10]=2)=[CH:18][CH:17]=1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN4C(=O)c5ccccc5C4=O)nc3)cc12
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN)nc3)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
A mixture of (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (57 mg, 0.089 mmol) and hydrazine, hydrate (8.29 μl, 0.266 mmol) in EtOH (2 mL) was heated to 70° C. for 10 minutes. THF (0.5 ml) was added to obtain homogeneity and heating was continued for 1.5 hr. Additional hydrazine, hydrate (8.29 μl, 0.266 mmol) (times 4; total of 12 equivalents) was added and heating was continued for 1.5 hr. A precipitation was observed. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated to a residue that was triturated with EtOAc. Filtration and drying afforded (3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (30 mg, 0.058 mmol, 66.0% yield) as a tan solid. The material is contaminated with the hydrazide by-product and will be used as is in the next step. MS (ES+) m/z: 514.4 (M+H); LC retention time: 2.303 min (analytical HPLC Method O).