Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH2:72]([N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:35])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:24]([CH3:26])[CH:25]=3)[C:36]([N:82]3[CH2:83][CH2:84][N:79]([CH2:72][C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)[CH2:80][CH2:81]3)=[O:38])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(Cc3ccccc3)CC2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1.54 g (2.69 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g), 952 mg (2.96 mmol) TBTU and 0.47 mL (3.37 mmol) triethylamine in 10 mL THF and 2 mL DMF the mixture was stirred for 1 h at RT. Then 0.52 mL (2.96 mmol) 1-benzyl-piperazine was added and the reaction mixture was stirred for another 14 h at RT. 30 mL EtOAc were added, the organic phase was washed with semisaturated NaHCO3 solution and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, EtOAc/Cyc 95:5), the fractions containing the product were combined, evaporated down, the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:14][F:15])([CH2:12][F:13])[CH2:6][C@@H:5]2O.N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CC(OC)(C)C>[N:42]([C@H:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][C:7]([CH2:14][F:15])([CH2:12][F:13])[CH2:6]1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CC(CF)(CF)Oc2ccc(F)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
A solution of Example 65B (54.1 mmol) in THF (190 mL) was cooled to <5° C. To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (12.1 mL, 81.0 mmol) followed by diphenylphosphoryl azide (15.2 mL, 70.3 mmol), keeping the temperature ≦5° C. (no exotherm). After stirring for 2 hours at ≦5° C., the reaction mixture was warmed to ambient temperature and stirred for 14 hours. The reaction mixture was diluted with MTBE (250 mL), washed with 2N NaOH (2×125 mL), brine (50 mL), 2N HCl (2×125 mL), and brine (50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, giving (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman (14.6 g, >100%) as a dark oil. The crude (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman in MeOH (300 mL) was added to 5% Pd—C (4.38 g) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 3 hours at 50° C. and 30 psi H2. Upon cooling, the reaction mixture was filtered through a nylon membrane and concentrated. The resulting residue was used without further purification. MS (DCI) m/z 232 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][CH:19]=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:27].[C:29](O)(=[O:32])[CH2:30][OH:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[OH:32][CH2:29][C:30]([NH:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][CH:19]=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:27])=[O:31]
Reactant: Cc1cc(CCC(=O)c2scc(CC(C)C)c2C)cc(C)c1OCC(O)CN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2scc(CC(C)C)c2C)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of rac-3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3-methyl-thiophen-2-yl)-propan-1-one (353 mg, 0.876 mmol) in DCM (10 mL), glycolic acid (127 mg, 1.67 mmol) followed by DIPEA (521 mg, 4.03 mmol) and TBTU (439 mg, 1.37 mmol) is added and the reaction mixture is stirred at rt for 16 h. The mixture is diluted with DCM and washed twice with water. The aq. washings are extracted three times with DCM. The combined organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with EA containing 0 to 100% of MeOH to give racemic 2-hydroxy-N-(2-hydroxy-3-{4-[3-(4-isobutyl-3-methyl-thiophen-2-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (160 mg) as a beige solid; LC-MS: tR=0.99 min, [M+1]=462.40; 1H NMR (D6-DMSO): δ 7.66 (t, J=5.9 Hz, 1H), 7.45 8s, 1H), 6.86 (s, 2H), 5.63 (s br, 1H), 5.26 (s br, 1H), 3.91-3.83 (m, 1H), 3.79 (s, 2H), 3.63-3.55 (m, 2H), 3.45-3.36 (m, 1H), 3.22-3.12 (m 1H), 0.310-3.04 (m, 2H), 2.80-2.73 (m, 2H), 2.40-2.37 (m, 5H), 2.15 (s, 6H), 1.76 (m, J=7.0 Hz, 1H), 0.85 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[I:26]N1C(=O)CCC1=O>C(O)(=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:26][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:2][CH:3]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Ic1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 98.8 %

Procedure:
3.2 g (10 mmol) of 9-(4-biphenylyl)carbazole was dissolved in a mixed solution of 200 mL of glacial acetic acid, 200 mL of toluene, and 50 mL of ethyl acetate. 2.3 g (10 mmol) of N-iodosuccinimide was slowly added thereto. The mixture was stirred overnight (for about 24 hours) and then washed with water, a sodium thiosulfate water solution, and a saturated sodium chloride solution. Magnesium sulfate was added thereto to remove water and filtered to obtain a filtrate. The filtrate was concentrated, mixed with acetone and hexane, and then recrystallized with ultrasonic wave. This was filtered to obtain a residue. The residue was collected and dried. 4.4 g (yield: 98%) of 3-iodo-9-(4-biphenylyl)carbazole, which was beige powder, was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNCCc1ccccc1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (3.4 g) in CH2Cl2 (50 mL) at 0° C. was treated sequentially with N-methylphenethylamine (2.4 mL), triethylamine (2.3 mL) and N,N-dimethylaminopyridine (162 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was washed with 1N HCl (1×100 mL) and brine (1×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (4.6 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:13][C@H:14]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C@H:15]2[C:26]([O:28]CC)=[O:27])=[O:12])=[CH:2]1.C1COCC1.CCO.[OH-].[Li+].Cl>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:13][C@@H:14]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C@H:15]2[C:26]([OH:28])=[O:27])=[O:12])=[CH:2]1
Reactant: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Cc1c[nH]c2ccccc12)N[C@@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O
Reaction time: 2.5 h
Yield: 25.7 %

Procedure:
To the title compound of example 8 (520 mg, 1.28 mmol) in 1:4 THF/EtOH (20 ml) was added lithium hydroxide (46 mg (1.92 mmol) in H2O (10 ml) and stirred for 2.5 h. The reaction mixture was acidified with 1N HCl to pH 3 and concentrated in vacuo. The mixture was purified by chromatography on silica gel (CH3OH/HOAc/CH2Cl2 gradient 10/1/89 to 20/1/79) to give 124 mg (18%) of the title compound. MS calcd for C21H19N3O4 : 377, found 377.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].C([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](=O)[CH3:24])=[C:15]1Cl)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O>CO.CCOC(C)=O>[CH2:16]([SH:1]1[C:15]2[NH:14][C:22]3[C:17]([C:16]=2[C:23]([CH3:24])=[C:2]1[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)c2c([nH]c3ccccc23)[SH]1Cc1ccccc1
Reaction time: 8 h

Procedure:
550 μl of methyl 2-mercaptoacetate was added to a slurry of 1.45 g of (82) and 1.6 g of K2CO3 in 15 ml of MeOH, and left with stirring overnight. 30 ml of water was added, and the product isolated as a sticky lump. This lump was dissolved in EtOAc, washed with water, dried and evaporated to give an oil, which slowly solidified. Crystallization from MeOH gave (83). Yield 330 mg. M.p. 132°-4° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.[CH:14]1([S:17]Cl)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([S:17][CH:14]2[CH2:16][CH2:15]2)=[N:8][CH:9]=1
Reactant: Brc1ccc(Br)nc1
Reactant: ClSC1CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Brc1ccc(SC2CC2)nc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
SO2Cl2 (9.8 mL, 122.0 mmol) was added slowly at 0° C. to dicyclopropyldisulfide (17.0 g, 116.2 mmol). The mixture was stirred at 20° C. for 2 h, before being diluted with anhydrous PhMe (100 mL) to give a PhMe solution of cyclopropanesulfenyl chloride. In a separate vessel, n-BuLi (153 mL of a 1.6M solution in hexanes, 244.8 mmol) was added to a stirred solution of 2,5-dibromopyridine (55.1 g, 232.4 mmol) in anhydrous PhMe (1L) at −78° C. After 3 h at −78° C., the abovementioned cyclopropanesulfenyl chloride solution was added slowly to the mixture. After 1 h, the mixture was quenched with saturated aqueous NH4Cl (1L) at −20° C., before being stirred at 20° C. for 16 h. The organic layer was separated, then the aqueous phase was extracted with Et2O (3×500 mL). The organic extracts were combined, dried (MgSO4), filtered, concentrated, and purified by flash column chromatography (IH-Et2O, 98.5:1.5) to furnish 5-bromo-2-cyclopropylsulfanylpyridine: m/z (ES+)=232.0 [M+H]+. Bromine-lithium exchange on this compound (22.0 g, 95.6 mmol) followed by reaction with diethyl oxalate, as described in Step 1 of Preparation 14, gave ethyl (6-cyclopropylsulfanylpyridin-3-yl)oxoacetate: m/z (ES+)=252.2 [M+H]+. Reaction of this oxoester (11.09 g, 44.1 mmol) with cyclopentylmethyltriphenylphosphonium iodide (33.00 g, 75.0 mmol), employing the protocol outlined in Step 3 of Preparation 14, provided ethyl 3-cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acrylate as a ca. 2:1 mixture of (E)- and (Z)-isomers: m/z (ES+)=318.2 [M+H]+. Using a similar procedure to that described in Step 4 of Preparation 14, this ester (13.21 g, 41.6 mmol) was hydrolysed to give the title compound: m/z (ES+)=290.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[Cl:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: O=C(O)c1csc(COc2ccc(-c3cccnc3Cl)cc2)n1

Procedure:
2-[4-(2-Chloro-pyridin-3-yl)-phenoxymethyl]-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 23 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 2-chloropyridine-3-boronic acid (available from Lancaster Synthesis Ltd., Morecambe, UK). Mass spectrum MH+=347.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]([CH:12]1[C:21](=O)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14][S:13]1)=[O:11]>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14][S:13]1)=[O:11]
Reactant: COC(=O)C1SCc2cc(OC)ccc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2ccc(OC)cc2CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Triethylsilane (8.08 mmol, 0.94 g) was added to a solution of 7-methoxy-isothiochroman-4-one-3-carboxylic acid methyl ester (0.51 g, 2.02 mmol) in trifluoroacetic acid (15 mL) at room temperature under N2. The reaction was allowed to stir at room temperature for 2 h and was concentrated under reduced pressure. The resulting oil was dissolved in EtOAc (100 mL) and washed with sat. NaHCO3 (3×75 mL). The organic extracts were combined, dried (MgSO4) and concentrated to provide an oil. The oil was purified on silica using medium pressure chromatography (9:1 petroleum ether/EtOAc) to provide 7-methoxy-isothiochroman-3-carboxylic acid methyl ester (0.34 g, 70%) as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ 3.14 (m, 2H), 3.58-3.63 (d, J=15 Hz, 1H), 3.73-3.86 (m, 8H), 6.70 (d, J=3 Hz, 1H), 6.75 (dd, J=3, 9 Hz, 1H), 7.10 (d, J=9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3[C:15](=[O:23])[O:16][C:17]([CH3:22])([C:19](O)=[O:20])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:24][N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:26].[B-](F)(F)(F)F.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:24][N:25]([CH3:26])[C:19]([C:17]1([CH3:22])[O:16][C:15](=[O:23])[C:14]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=[N:12][C:13]=2[CH2:18]1)=[O:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C(=O)O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1(C)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reaction time: 48 h
Yield: 40 %

Procedure:
To 50 mg (0.15 mmol) of 44 in 2 mL of DMF is added 58 mg (0.18 mmol) of TBTU, 15 mg (0.18 mmol) of dimethylamine hydrochloride and 0.03 mL (0.2 mmol) of iPr2NEt. The mixture is stirred for 48 h, diluted with 50 mL of EtOAc, and washed twice with 20 mL of H2O and once with 20 mL of brine. The organic phase is dried with MgSO4, filtered, concentrated, and purified twice by preparative TLC (100% EtOAc) to give 22 mg (0.06 mmol) of 46.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([O:14]C)=[O:13])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[OH-].[Na+].C(OCC)C>O1CCOCC1.CO>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:7]3[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=3[C:5]([C:12]([OH:14])=[O:13])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Reactant: Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Temperature: 110 °C

Procedure:
To a suspension of methyl 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (23.1 g) in 1,4-dioxane (300 ml) was added 3-chloroaniline (27 ml). The reaction was heated at 110° C. for 17 hours during which time a solution was rapidly formed upon heating followed by the precipitation of a solid. The reaction was allowed to cool and then partitioned between dichloromethane (700 ml) and saturated sodium carbonate (500 ml). The aqueous layer was separated and further extracted with dichloromethane (300 ml). The organic extracts were combined and dried (MgSO4). This was then combined with another dichloromethane extract of a reaction conducted as above (weight of methyl 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate is 22.9 g). The solvent was removed to yield an orange/brown solid. This was heated in methanol (650 ml) and 2N sodium hydroxide (350 ml) to 80° C. and stirred for 3 hours. The reaction was cooled and then reduced in vacuo. The residue was stirred with diethyl ether (400 ml) for 15 minutes. The orange liquid was decanted and the solid residue triturated with diethyl ether (400 ml). The solid was filtered then added to water (400 ml). The solution was altered in pH to around 7 with 5N hydrochloric acid. The precipitate was filtered, however was in the form of a sticky gum. All material was transferred into a flask with methanol (>1 L in total). The solution was reduced in vacuo. A precipitate formed after the majority of the methanol had been removed. This was filtered and dried in vacuo to yield the title compound (60.23 g).
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13](O)=[O:14]>C1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([Cl:8])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
1 ml of dimethyl formamide and 17.9 gm (0.15 mol) of thionyl chloride were added to a suspension of 20.1 gm (0.1 mol) of 2-chloro-6-nitro-benzoic acid in 150 ml of anhydrous benzene. The reaction mixture was stirred for 30 minutes and heated to reflux temperature. After 3 hours another 17.9 gm (0.15 mol) of thionyl chloride were added. The reaction mixture was further refluxed for 3 hours. After cooling, the reaction mixture filtered, and the filtrate was evaporated in vacuo.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:8].[S:18]1[C:22]2[CH2:23][CH:24]([NH2:27])[CH2:25][CH2:26][C:21]=2[N:20]=[CH:19]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N.C([O-])(O)=O.[Na+]>C(#N)CC.C(Cl)Cl>[S:18]1[C:22]2[CH2:23][CH:24]([NH:27][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[O:8])[CH2:25][CH2:26][C:21]=2[N:20]=[CH:19]1
Reactant: NC1CCc2ncsc2C1
Reactant: O=C(NCCCCO)c1nc2ccccc2s1
Agent: C[P+](C)(C)CC#N
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCCNC1CCc2ncsc2C1)c1nc2ccccc2s1
Temperature: 90 °C

Procedure:
To a solution of 339 mg (1.4 mmol) N-(4-hydroxybutyl)benzothiazole-2-carboxamide, 198 mg (1.2 mmol) 4,5,6,7-tetrahydro-benzothiazol-6-yl-amine and 210 mg (1.6 mmol) DIPEA in 6 mL of propionitrile is added 0.39 g (1.6 mmol) cyanomethyltrimethylphosphonium iodide under argon. The mixture is heated for 2 hours at 90° C. After cooling down to room temperature 10 mL of saturated NaHCO3 solution and 20 mL of CH2Cl2 are added. The organic phase is extracted with 10 mL of water three times. After drying and removing of the solvent in vacuum the brown oil received is purified via silica gel chromatography.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:8]1.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][CH:29]=1.CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][C:16]([NH:33][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:31])=[O:32])=[O:18])[CH2:11][CH2:12]1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)CCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)CCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 12.8 %

Procedure:
4-(3,4-Dichlorophenoxy)-1-piperidinebutanoic acid hydrochloride (0.250 g) was dissolved in dichloromethane (10 mL) containing p-toluenesulfonamide (0.142 g), dimethylaminopyridine (92 mg) and EDCI (0.158 g) were added. The solution was stirred at room temperature for 4 days. The solvent was evaporated. The crude product was dried in vacuo and then purified by HPLC (at column dilution, gradient ammonium acetate/acetonitrile 75% to 5% ;Waters Xterra® column) and to give the title compound (42 mg).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[N:14]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH:11][CH:10]=1.Br[C:29]1[N:33]2[N:34]=[C:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])[CH:36]=[CH:37][C:32]2=[N:31][CH:30]=1>C1(C)C=CC=CC=1>[F:50][C:44]1[CH:45]=[CH:46][C:47]([F:49])=[CH:48][C:43]=1[CH:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:35]1[CH:36]=[CH:37][C:32]2[N:33]([C:29]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([F:8])[N:14]=3)=[CH:30][N:31]=2)[N:34]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)n1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(-c4cccc(F)n4)n3n2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In step 5-1, triethylamine (0.045 mL, 0.29 mmol), tetrakis(triphenylphospine)palladium (0) (12 mg, 0.01 mmol), and 6-fluoro-2(tributylstannyl)pyridine (80 mg, 0.201 mmol) were added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (53 mg, 0.13 mmol) in 3 mL of toluene. The reaction mixture was heated to 100° C. and stirred for 6 hours at 100° C. The reaction mixture was then cooled to room temperature and purified using flash chromatography (ethyl acetate and hexanes (1:1)) giving 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (5-1). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.35-8.17 (m, 2H), 8.02-7.83 (m, 1H), 7.48-7.22 (m, 3H), 7.15-6.92 (m, 3H), 5.42 (br d, J=5.8 Hz, 1H), 4.12-3.99 (m, 1H), 3.81-3.72 (m, 1H), 2.70-2.56 (m, 1H), 2.30-2.06 (m, 3H). LCMS observed m/z 396.1
Reaction SMILES: NC1N=C(C=O)C=CN=1.C[O:11][CH:12](OC)[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=1>>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([CH:12]=[O:11])[CH:18]=[CH:17][N:16]=1
Reactant: CNc1nccc(C(OC)OC)n1
Agent: Nc1nccc(C=O)n1
Product: CNc1nccc(C=O)n1
Yield: 30 %

Procedure:
2-Methylaminopyrimidine-4-carboxaldehyde (I-11) was synthesized in a similar manner to 2-aminopyrimidine-4-carboxaldehyde (I-9, procedure I). Reaction of crude 2-methylaminopyrimidine-4-carboxaldehyde dimethyl acetal (I-10) from procedure J provided 1.7 g (30% from dimethylformamide dimethyl acetal) of 2-methylaminopyrimidine-4-carboxaldehyde (I-11) as dark brown foam.