Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2ON1C2C=CC=CC=2N=N1)(=[O:3])[CH3:2].[F:35][C:36]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=1[NH2:38]>>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:38][C:37]1[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:36]=1[F:35])(=[O:3])[CH3:2]
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1ccc(Cl)cc1F
Product: C#C[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C

Procedure:
(2R,3R,4R,5R)-4-(acetyloxy)-2-[6-(1H-1,2,3-benzotriazol-1-yloxy)-9 H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate was treated with 2-fluoro-4-chloroaniline (0.63 ml), and the mixture was heated at 60° C. for 22.5 h. The mixture was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate:cyclohexane 10:90-60:40, to give the title compound (55 mg).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:13]CC1C=CC=CN=1>>[C:3]([NH2:13])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCc1ccccn1
Reactant: O=C(c1ccccc1)C(Cl)(Cl)Cl
Product: NC(=O)c1ccccc1

Procedure:
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-.,a-dichloroacetophenone as an intermediate by chlorinating the a-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60° C. The α,α-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100° C. to yield the α,α,α-trichloroacetophenone. The α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([N:25]2[CH:29]=[N:28][N:27]=[C:26]2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[N:13]2>ClC(Cl)(Cl)C>[Cl:9][C:10]1[C:11]([N:25]2[C:29]([Br:1])=[N:28][N:27]=[C:26]2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[N:13]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Solvent: CC(Cl)(Cl)Cl
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(Br)nnc3-c3cccnc3)c2nc1OC
Yield: 72.2 %

Procedure:
N-Bromosuccinimide (58 mg, 0.33 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-[3-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 98, 102 mg, 0.25 mmol) in 1,1,1-trichloroethane (6 mL) at room temperature under nitrogen and the mixture was heated under reflux for 18 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel, by gradient elution using hexane:ethyl acetate (7:3 changing to 1:1, by volume) to give the title compound (87 mg, 71%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[CH3:13]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(C)cc1N
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 1-fluoro-5-methoxy-2-methyl-4-nitro-benzene (5.5 g, 29.3 mmol) and 10% Pd-C (1.56 g) in ethanol (300 mL, 0.1 M) was hydrogenated at 1 atm. After stirring overnight, the solution was flushed through a pad of silica gel using 400 mL of ethanol as the eluant. The filtrate was concentrated under reduced pressure to afford 4-fluoro-2-methoxy-5-methyl-phenylamine (4.5 g, 99%) as a pale purple solid: mp 108-110° C.; Rf 0.35 (30% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 6.62 (d, J=11.4 Hz, 1H)', 6.43 (d, J=7.8 Hz, 1H), 3.70 (s, 3H), 2.02 (d, J=1.8 Hz, 3H); ESI-LC/MS m/z calcd for C8H10FNO: 155.1; Found 156.0 (M+1)+. Anal. calcd for C8H10FNO: C, 61.92; H, 6.50. Found: C, 61.64; H, 6.53.
Reaction SMILES: ClC1C=C(C[CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40]CC(O)=O)=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][CH:28]1[CH2:29][CH2:30][CH:25]([N:11]([CH2:10][CH2:9][CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: Cc1ccc(CCCC(=O)O)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: Cc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methyl-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH2:11])=[CH:9][N:10]=2.[CH3:13][O:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][C:16]=1[OH:30].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.FC1(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C1(F)F>[NH2:11][C:8]1[N:7]=[C:6]2[N:12]=[C:2]([C:19]3[CH:18]=[CH:17][C:16]([OH:30])=[C:15]([O:14][CH3:13])[CH:20]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Nc1cnc2ccc(Cl)nc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2ccc3ncc(N)nc3n2)ccc1O
Temperature: 75 °C
Reaction time: 7.5 h
Yield: 94.1 %

Procedure:
To a suspension of 1.13 g 6-Chloro-pyrido[2,3-b]pyrazin-3-ylamine (5.94 mmol; 1 eq) and 1.67 g 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (6.55 mmol; 1.1 eq.) in ethylene glycol dimethyl ether (45 mL) under Ar, a solution of 6.29 g sodium carbonate (59.3 mmol; 10 eq.) in water (20 mL) and a suspension of 378 mg FluoroFlash catalyst (0.24 mmol; 0.04 eq.) in undecafluoro(trifluoromethyl)cyclohexane (45 mL) were added. The mixture was heated to 75° C. for 5 hours. Additional 0.76 g (2.97 mmol; 0.5 eq) of 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol were added and the resulting mixture was stirred at 75° C. for 7.5 hours. After cooling to room temperature, the aqueous and organic phase were separated from the fluorous phase and concentrated in vacuo. The residue was dissolved in methanol and methylene dichloride and filtered. The black solution was again concentrated in vacuo. The residue was taken up in water and the resulting solution was neutralized with 1 N HCl whereas the product crystallizes. The brown solid was filtered of, washed with water and dried in vacuo to afford 1.5 g (80.2% yield) of 4-(3-Amino-pyrido[2,3-b]pyrazin-6-yl)-2-methoxy-phenol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[OH:4].C=O.[C:21](O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:21][NH:1][CH2:2][CH:3]2[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OC1CNCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
To 10 g (41 mmol) 2-amino-1-[3-(benzyloxy)phenyl]ethan-1-ol and 4.6 mL (62 mmol) formaldehyde (37% solution in water) in 100 mL DCM are added slowly 6.3 mL (82 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction is neutralised by the addition of a sat. aq. NaHCO3 solution and extracted with DCM. The organic layer is washed with a sat. aq. NaCl solution, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CN[C@H]1[C@H](NC)CCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13](=[O:14])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(=O)c(-c2ccc(F)cc2)c1
Reactant: Brc1ccccn1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(-c2ccccn2)c1
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 5-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (77.0 mg, 0.31 mmol) in dioxane (2.1 mL) were added 2-bromopyridine (0.15 g, 0.92 mmol), trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexanediamine (17.7 mg, 0.13 mmol) and potassium carbonate (86.0 mg, 0.62 mmol). The mixture was heated in the microwave reactor at 120° C. for 1 h then heated in an oil bath at 80° C. for 8 h. The mixture was cooled to ambient temperature and dichloromethane was added. The mixture was washed with water, sat. NaHCO3, brine and dried with sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→75% dichloromethane/ethyl acetate) gave the title compound (94 mg). MS 325.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14](O)=[O:15])=[CH:12][C:11]([O:17][CH2:18][C:19]#[CH:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([Cl:24])=[O:15])=[CH:12][C:11]([O:17][CH2:18][C:19]#[CH:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C#CCOc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCOc1cc(C(=O)Cl)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a 100 mL flask, 1-(3,5-dichloropyridin-2-yl)-3-(prop-2-ynyloxy)-1H-pyrazole-5-carboxylic acid (0.2 g, 0.64 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.16 g, 1.2 mmol) were added. After five drops of N,N-dimethyl formamide were added, a large number of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was evaporated to dryness at reduced pressure. Then 100 mL toluene was added, and the reaction mixture was concentrated again under reduced pressure to give the product (0.21 g) as yellow solid in 100% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:9](=[N:8][C:7]#[N:6])[S:13][CH3:14])[N:8]=1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CSC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 147.5 %

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidine (180 mg.) in acetonitrile (2 ml.) was treated with dimethyl (cyanoimidio)dithiocarbonate (85 mg.) and the solution stood at room temperature for 18 hours. The crystalline solid which precipitated was collected to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine (175 mg.), m.p. 189°-190°.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[N:7][CH:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC>>[CH:6](=[N:7][CH:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])[C:5]1[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)C(N=Cc1ccc(Br)cc1)C(C)C
Agent: [Li]CCCC
Product: CC(C)C(N=Cc1ccccc1)C(C)C

Procedure:
treating (4-bromobenzylidene) (1-isopropyl-2-methylpropyl)amine with n-butyllithium to give para-lithiated (benzylidene) (1-isopropyl-2-methylpropyl)amine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34]3[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=3)=[N:31][N:30]=2)=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:19]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:33][C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH2:38][NH:11][C@@H:9]4[CH2:10][C@H:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]4)=[CH:40][CH:41]=3)=[N:31][N:30]=2)=[CH:27][CH:28]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Reactant: CC(C)Cc1ccc(-c2nnc(-c3ccc(C=O)cc3)o2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nnc(-c4ccc(CC(C)C)cc4)o3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of cis-3-amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.181 g, 1.01 mmol), triethylamine (0.10 mL, 0.72 mmol) and dichloromethane (8 mL) was stirred at room temperature for 30 minutes. 4-[5-(4-isobutylphenyl)-1,3,4-oxadiazol-2-yl]benzaldehyde (0.181 mg, 1.04 mmol) was added to the reaction mixture and stirred for 2 hours. Sodium triacetoxyborohydride (0.213 g, 1.01 mmol) was added to the reaction mixture and stirred for 16 hours. Additional cis-3-amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.100 mg, 0.773 mmol) and sodium triacetoxyborohydride (0.213 g, 1.01 mmol) was added to the reaction mixture and stirred for 72 hours. The reaction mixture was concentrated in vacuo and the resulting residue was triturated with water, filtered and dried to provide the title compound (0.303 g, 88% yield) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:7][C:6]=1[O:24][CH3:25])(=[O:3])[CH3:2].C(OC1C=CC(CCO)=CC=1OC)(=O)C.[I-:41].[Na+]>CC(C)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][I:41])=[CH:7][C:6]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: COc1cc(CCOS(=O)(=O)c2ccc(C)cc2)ccc1OC(C)=O
Reactant: [I-]
Agent: COc1cc(CCO)ccc1OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(CCI)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6:4 mixture of 2-methoxy-4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl acetate and 4-(2-hydroxyethyl)-2-methoxyphenyl acetate (1.57 g, 4.31 mmol) and sodium iodide (0.706 mL, 17.2 mmol) in dry acetone (28 mL) was stirred at room temperature overnight with protection from light. The acetone was removed in vacuo and the residue was triturated with toluene and filtered through a plug of Celite to remove insoluble inorganic material. The filtrate was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 50% EtOAc in hexanes over 4536 mL) to give 4-(2-iodoethyl)-2-methoxyphenyl acetate. Rf=0.58 (20% EtOAc/hexanes). LCMS calc.=321.0; found=320.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:41][S:42]([O:38][C@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in pyridine (0.12 M) was added MsCl (7.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 45% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.60 min.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][S:24]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: OCCCCc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.59 g (7.0 mmol) of 5-(4-hydroxybutyl)imidazo[1,2-a]pyridine hydrochloride and 2.25 ml (16 mmol) of triethylamine in 30 ml of dichloromethane, 0.62 ml (8.0 mmol) of methanesulfonyl chloride was added at 0° C. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added. The reaction mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 5-(4-methanesulfonyloxybutyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:32]([NH2:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:32]([NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[CH:17]=2)[CH2:19]1)=[O:26])[CH3:33]
Reactant: CCN
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 8.3 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), ethylamine (11 mg, 0.236 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 25-35% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (8.8 mg, 8%). Melting point (227.8-228.7° C.). 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.05 (t, J=5.4 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.56-7.65 (m, 2H), 7.41 (s, 1H), 6.36 (d, J=2.3 Hz, 1H), 4.31 (br. s., 2H), 3.29 (dd, J=12.0, 10.5 Hz, 2H), 2.93-3.17 (m, 4H), 1.92 (br. s., 1H), 1.77-1.87 (m, 1H), 1.73 (br. s., 2H), 1.45 (s, 6H), 1.02 (t, J=7.3 Hz, 3H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[C:10]([C:18]([OH:20])=[O:19])[C:9]=2[O:21][CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl.[CH2:26](O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:26][CH3:27])=[O:16])=[C:10]([C:18]([OH:20])=[O:19])[C:9]=2[O:21][CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: COc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c(OC)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
5-(p-Chlorobenzoyl)-3-hydroxycarbonyl-4-methoxy-1-methylpyrrole-2-acetic acid (478 mg) is suspended in 5 ml of absolute ethanol under nitrogen and heated to reflux. Concentrated hydrochloric acid (75 ml) is subsequently added and the reaction mixture is heated for another 20 minutes until all the solids are dissolved. The resulting solution is heated for an additional 10 minutes. Upon cooling, the product crystallizes out and is filtered, and dried in vacuo to afford 260 mg of ethyl 5-(p-chlorobenzoyl)-3-hydroxycarbonyl-4-methoxy-1-methylpyrrole-2-acetate, m.p. 190 (dec.)
Reaction SMILES: [I:1][Si](C)(C)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14]([NH:15][C@@H:16]3[CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][C@@:17]3([F:32])[CH3:31])=[C:13]([C:33](=[O:35])[NH2:34])[CH:12]=[N:11][N:10]2[CH:36]=1>C(#N)C>[IH:1].[Br:6][C:7]1[CH:8]=[C:9]2[C:14]([NH:15][C@H:16]3[C@:17]([F:32])([CH3:31])[CH2:18][NH:19][CH2:20]3)=[C:13]([C:33]([NH2:34])=[O:35])[CH:12]=[N:11][N:10]2[CH:36]=1
Reactant: C[Si](C)(C)I
Reactant: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: CC#N
Product: C[C@]1(F)CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Product: I
Reaction time: 1 h
Yield: 105.5 %

Procedure:
Iodotrimethylsilane (0.134 mL, 0.938 mmol) was added dropwise to a solution of (3S,4R)-benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (115 mg, 0.235 mmol) in acetonitrile (3 mL). After 1 h at room temperature, the mixture was quenched with methanol (1 mL) and concentrated in vacuo. The solid residue was triturated with diethyl ether (3 mL) and filtered. The filter cake was rinsed with diethyl ether and dried under vacuum to give crude 6-bromo-4-(((3R,4S)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (120 mg), which was used in the next step without further purification. MS (ES+) m/z: 356.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([O:10][C:11](SC1N=C(C)C=C(C)N=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CO>[C:6]([O:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: NCCCO
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCO
Reaction time: 6 h
Yield: 84.2 %

Procedure:
Into 30 ml of methanol, was dissolved 1.5 g (20 mmoles) of 3-amino-1-propanol followed by the addition of 4.8 g (20 mmoles) of S-tert-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimdine (a product of Kokusan Kagaku Co.). After stirring for 6 hours, the reaction mixture was evaporated to drynes, dissolved in 200 ml of chloroform, and washed with 200 ml of water. The chloroform layer was concentrated and subjected to column chromatography using 300 g of silica gel (Wako Gel® C-200) and a toluene-ethyl acetate (1:1 by volume) mixture as a developing solvent. The Fraction Nos. 82 to 151 (each 15 ml in volume) were combined and evaporated to obtain 2.95 g (84% yield) of 3-tert-butoxycarbonylamino-1-propanol in the form of colorless oil.