Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(O)(C(F)(F)F)=O.CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[NH:5][CH:4]=[CH:3]2
Reactant: COC(CNc1ccc(Cl)c(OCCN(C)C)c1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1cc2[nH]ccc2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
A solution of N-[4-chloro-3-(2-dimethylaminoethoxy)phenyl]aminoacetaldehyde dimethyl acetal (D7, 0.61 g, 0.002 mol) in TFA (2.6 ml) at 0° C., was treated with TFAA (2.6 ml) under an argon atmosphere. More TFA (3.7 ml ) was added and the reaction was heated to reflux for 48 h. The solution was evaporated to dryness and the residue taken up in EtOAc. The extract was dried (Na2SO4) and concentrated in vacuo to leave a brown oil which was dissolved in MeOH (10 ml), treated with K2CO3 (1 g) and then stirred at room temperature for 3 h The mixture was concentrated in vacuo, and then the residue treated with water and extracted with EtOAc. The solution was dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown solid (0.37 g , 76%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccc([N+](=O)[O-])c2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 3-nitrobenzaldehyde (57) (0.302 g, 2 mmol) afforded, after workup, a yellow solid. The crude product was recrystallized from dichloromethane-petroleum ether to afford 0.82 g (1.53 mmol, 77%) of 68 as a light yellow crystalline solid: mp 175°-178° C.; IR (CH2Cl2) 3440, 2980, 1695, 1620, 1550, 1532, 1470, 1350, 1295, 1210, 1100, 905, 810 cm-1 ; 1H NMR (CDCl3) δ 1.11 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H), 2.29 (s, 6H), 3.32 (s, 3H), 3.58 (t, J=4.8 Hz, 2H), 4.20 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.09 (s, 1H), 6.46 (s, 1H), 7.32-9.28 (m, 9H); 13C NMR (CDCl3) δ 19.38, 19.48, 21.97, 22.20, 40.09, 58.82, 62.85, 67.28, 70.72, 102.95, 103.74, 119.45, 121.46, 123.39, 124.88, 128.68, 129.76, 130.68, 132.25, 132.37, 134.13, 144.77, 145.57, 148.44, 148.61, 149.94, 166.96, 167.43; mass spectrum, m/e (relative intensity) 537 (M+, 0.1), 296 (100), 254 (66.6), 196 (67.2), 150 (15.8), 59 (20.6), 43 (21.1), 28 (73.7). Anal. Calcd for C28H31N3O8 : C, 62.57; H, 5.77. Found: C, 62.74; H, 5.60.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([O:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]=[O:24])[CH:12]=[N:11][C:10]=2[N:9]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1=[O:33])=[O:4].[Cl:36]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:36][C:12]1[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[O:24])[C:14]2[C:15](=[O:16])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])[C:8](=[O:33])[N:9]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])[C:10]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2c(ncn2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1c(=O)c2c(nc(Cl)n2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2,2-Dimethylpropionic acid [1-(2,2-dimethylpropionyloxymethyl)-7-(2-formylphenyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (2.50 g) and N-chlorosuccinimide (896 mg) were dissolved in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 2.0 g of the title compound from the elution fraction of hexane-ethyl acetate (2:1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13](=[O:21])[NH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]1=[O:21]
Reactant: O=c1[nH]cc(-c2ccc(Cl)cc2)n1-c1ccccc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.05 g of NaH (80% suspension in mineral oil), 9.5 g of 5-(4-chlorophenyl)-1-phenyl-4-imidazolin-2-one, 70 cc. of DMF, 8.3 g of 8-bromocaprylic acid methyl ester and 1.05 g of NaJ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:52]=[C:53]([O:57][CH3:58])[C:54]=1[O:55][CH3:56])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:34]([CH2:35][C:36]4[N:37](CC5C=CC=CC=5)[CH:38]=[CH:39][N:40]=4)[C:33]4[CH:48]=[CH:49][CH:50]=[CH:51][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:58][O:57][C:53]1[CH:52]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:54]=1[O:55][CH3:56])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:34]([CH2:35][C:36]4[NH:40][CH:39]=[CH:38][N:37]=4)[C:33]4[CH:48]=[CH:49][CH:50]=[CH:51][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4nccn4Cc4ccccc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ncc[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(1-benzyl-1H-imidazol-2-ylmethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl) pyrrolidine (5 mmol) and 10% palladium-on-carbon (1.5 g) in methanol (50 mL). Add anhydrous ammonium formate (25 mmol). Heat to reflux. After 18 hours, filter, rinse with dichloromethane, and evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)cc1F
Temperature: 90 °C
Yield: 60.7 %

Procedure:
A mixture of 3,4-difluorobenzaldehyde (4.26 g, 30 mmol) and sodium thiomethoxide (2.1 g, 30 mmol) in DMF (40 mL) was heated at 90° C. for 1 hour. After cooling, 2N aqueous HCl was added to the mixture. The whole was extracted with Et2O (70 mL×3), the combined organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/10) to provide the subtitle compound (3.1 g, 61% yield) as a colorless oil.
Reaction SMILES: Cl[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH2:22][CH2:23][C:24]#[CH:25].CO>CN(C=O)C>[C:16]1([C:2]2([NH:22][CH2:23][C:24]#[CH:25])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[O:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: C#CCN
Solvent: CO
Solvent: CN(C)C=O
Product: C#CCNC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reaction time: 3 h
Yield: 81.6 %

Procedure:
9-Chloro-9-phenylxanthen (14.7 g, 50 mmol) was added in two equal portions over 0.5 h to a stirred solution of 3-aminopropyne (8.6 mL, 125 mmol) in DMF (100 mL). After 3 h, MeOH (20 mL) was added and the reaction mixture was stirred for 15 min. The mixture was then extracted into diethyl ether (500 mL) and washed with H2O (3×300 mL), dried (Na2SO4), and the solvent removed under vacuum. The resulting yellow oil was dried under high vacuum (4 h), and then redissolved in hot diethyl ether (70 mL). The solution was kept at -20° C. for 24 h and then filtered, the solid washed with ice-cold hexand (2×50 mL) followed by ice-cold diethyl ether (2×50 mL), giving 12 as a colourless powder (12.7 g, 82%), mp 116-8° C. 1H NMR (d6 -DMSO): δ2.86 (dd, 2H, H3, J=7.3, 4.4 Hz), 2.99 (t, 1H, H1, J=2.4 Hz), 4.01 (t, 1H, NH, J=7.2 Hz), 6.98-7.50 (m, 13H, Px CH). 13C NMR (d6 -DMSO): δ32.8 (C3), 59.7 (Px C9), 73.4 (C1), 82.7 (C2), 1160.0 and 123.5 (Px CH), 125.0 (Px C8a and C9a), 126.3, 126.4, 128.0, 128.6, 128.7 (Px CH), 149.5 (Px C1'), 150.7 (Px C4a and C10a). FABMS m/z 311 (M+). Anal. calcd for C22H17NO: C, 84.8; H, 5.51; N,4.50. Found: C, 84.4; H. 5.73; N, 4.30.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[CH3:25])=[CH:4][C:3]=1[F:26].BrC1C=C(F)C(N)=C(F)C=1.CC1C2C(=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)N(C(OC(C)(C)C)=O)N=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[CH3:25])[CH:4]=[C:3]([F:26])[C:2]=1[NH2:1]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(-c3cc(F)c(N)c(F)c3)cc12
Agent: Cc1nn(C(=O)OC(C)(C)C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Nc1c(F)cc(Br)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3cc(F)c(N)c(F)c3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 317.8 %

Procedure:
Following the general procedure-1, tert-butyl 5-(4-amino-3,5-difluorophenyl)-3-methyl-1H-indazole-1-carboxylate (106 mg) was prepared from 4-bromo-2,6-difluoroaniline (250 mg, 1.2 mmol) and teRT-butyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (559 mg, 1.56 mmol) as a white solid. teRT-butyl 5-(4-amino-3,5-difluorophenyl)-3-methyl-1H-indazole-1-carboxylate (205 mg) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (0.8 ml) was added and stirred at RT for 4 h. The solvent was removed and the residue co-evaporated 4 times with dichloromethane. Solid obtained was dried under high vacuum to obtain the title compound (243 mg) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.01 (bs, 1H), 7.92 (s, 1H), 7.58 (dd, J 1.4, 8.7, 1H), 7.44 (d, J 8.7, 1H), 7.32 (dd, J 2, 8.2, 2H), 5.22 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:24]1[C:28]([C:29](O)=[O:30])=[CH:27][C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]1=2>>[S:24]1[C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[OH:20])[CH2:11]3)[CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3]2)=[O:30])=[CH:27][C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]1=2
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: O=C(O)c1cc2ccccc2s1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3s2)CC1)C1CCc2c(O)cccc2C1
Yield: 99.9 %

Procedure:
Compound 40i was prepared following Procedure G using 39b (175 mg, 0.551 mmol) and benzo[b]thiophene-2-carboxylic acid (118 mg, 0.661 mmol) to give 40i (263 mg, 64%) after column chromatography. 1H NMR (400 MHz, CD3OD) 0.91-0.97 (t, 3H, J=7.2 Hz), 1.53-1.68 (m, 3H), 2.50-2.63 (m, 7H), 2.78-3.02 (m, 7H), 3.77-3.79 (bs, 4H), 6.55-6.59 (t, 2H, J=8 Hz), 6.89-6.93 (t, 1H, J=8.4 Hz), 7.40-7.46 (m, 2H), 7.61 (s, 1H), 7.85-7.91 (m, 2H). The free base of 40i was converted into its HCl salt. m.p. 131-134° C. Anal. [C28H35N3O2S.2HCl.1.5H2O] C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5]O.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][Cl:16]
Reactant: OCc1ccc(C(F)(F)F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1cc(CCl)ccc1C(F)(F)F
Yield: 86.1 %

Procedure:
To absolution of 3-fluoro-4-(trifluoromethyl)benzyl alcohol (10 g, 52 mmol) in chloroform (20 ml) was added thionyl chloride (18.5 ml, 257 mmol) and the mixture was heated under ref lux for 4 hrs. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-fluoro-4-(trifluoromethyl)benzyl chloride (9.52 g, 87%).
Reaction SMILES: [O:1]=O.[C:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([N+:16]([O-:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)([OH:5])=[O:4]>C(O)(=O)C>[C:3]([C:6]12[CH2:15][C:10]3([OH:1])[CH2:11][CH:12]([CH2:14][C:8]([N+:16]([O-:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)([OH:5])=[O:4]
Reactant: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reactant: O=O
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(O)(C1)CC([N+](=O)[O-])(C3)C2
Yield: 80 %

Procedure:
In an atmosphere of oxygen, the mixture of 10 mmole of 1-carboxy-3-nitroadamantane, 1 mmole of NHPI, 0.05 mmole of V(AA) 3 and 25 mL of acetic acid was allowed to react for 4 hours at 85° C. The reaction products were analyzed by gas-mass spectroscopy, and as a result, 1-carboxy-3-nitro-5-adamantanol was formed in a 80% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]([C:15]([O:17]C)=O)=[CH:8][CH:7]=1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C@H:28]1[CH2:31][C@H:30]([NH2:32])[CH2:29]1.C1(C2CCCCCCCCC=2)CCCCCCNNN=1>C1COCC1.C(Cl)Cl>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C@H:28]1[CH2:29][C@H:30]([NH:32][C:15]([C:9]2[C:10]3[N:11]([CH:12]=[CH:13][N:14]=3)[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)=[O:17])[CH2:31]1
Reactant: N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Reactant: COCOCc1ccc(C(=O)OC)c2nccn12
Agent: C1=C(C2=NNNCCCCCC2)CCCCCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCOCc1ccc(C(=O)N[C@H]2C[C@H](Oc3cccc(Cl)c3Cl)C2)c2nccn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (438 mg, 1.75 mmol), trans-3-[(2,3-dichlorophenyl)oxy]cyclobutanamine (463 mg, 1.995 mmol) and triazabicyclodecene (75 mg, 0.539 mmol) in THF (0.5 mL) was stirred in a sealed tube at room temperature for 18 hours. The reaction mixture was then transferred to a round bottomed flask using DCM as solvent and evaporated in vacuo to give yellow/brown gum which solidified (1.5 g). This material was dissolved in DCM and purified on silica (70 g) using a 0-100% ethyl acetate-cyclohexane gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as yellow crystals (601 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:19]([OH:21])=O)[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:26]([NH:25][CH2:24][CH2:23][NH:22][C:19]([C:7]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH2:1])=[O:21])(=[O:28])[CH3:27]
Reactant: CC(=O)NCCN
Reactant: Nc1ncnc2c(C(=O)O)cc(-c3cccc(F)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NCCNC(=O)c1cc(-c2cccc(F)c2)cc2c(N)ncnc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a 4 mL screw-cap vial was added 4-amino-6-(3-fluorophenyl)quinazoline-8-carboxylic acid (0.10 mmol, 28 mg) followed by N-(2-aminoethyl)acetamide (2 equiv., 0.20 mmol, 20 mg), HATU (1.1 equiv., 0.11 mmol, 43 mg), dimethylformamide (0.5 mL), and triethylamine (3 equiv., 0.30 mmol, 0.042 mL). The reaction was capped and shaken at 50° C. for 4 h. The reaction was cooled to room temperature, diluted with 2.5 ml dichloromethane and washed with 1 ml water. Organic was concentrated, then the crude was purified by reverse phase HPLC, yielding 6 mg of desired product. 1H NMR (400 MHz, DMSO) δ 11.17-11.07 (t, J=5.6 Hz, 1H), 8.89-8.75 (m, 2H), 8.54-8.50 (s, 1H), 8.44-8.06 (m, 2H), 8.06-7.99 (t, J=5.5 Hz, 1H), 7.75-7.64 (m, 2H), 7.64-7.53 (m, 1H), 7.35-7.22 (m, 1H), 3.53-3.44 (m, 2H), 3.32-3.26 (m, 2H), 1.85-1.82 (s, 3H). LCMS M/Z (M+H)=368.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:31][N:32]=2)[N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([C:33]3[CH:37]=[N:36][N:35]([CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[CH:34]=3)=[CH:31][N:32]=2)[N:29]=1
Reactant: ClCCN1CCOCC1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(-c4cn[nH]c4)n3n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(-c4cnn(CCN5CCOCC5)c4)n3n2)c1
Temperature: 25 °C

Procedure:
In step 7-2, 4-(2-chloroethyl)morpholine hydrochloride (40 mg, 0.2 mmol) was added to a solution of 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (7-1) (35 mg, 0.1 mmol) and cesium carbonate (100 mg, 0.35 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature over-night and the DMF was then removed using a rotary evaporator. The resulting residue was reconstituted in ethyl acetate (30 mL) and the organic layer extracted with brine and then dried using sodium sulfate. The ethyl acetate was removed and the product was further purify by preparative LC/MS to yield 4-(2-(4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine (7-2) as a white solid. m/z=480.2 [M+1].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:13]/[O:14][CH2:15][C:16]1[O:17][CH:18]=[C:19]([O:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:22])[CH:21]=1)/[C:7]([O:9]CC=C)=[O:8].C(C(CCCC)C([O-])=O)C.[Na+:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:13]/[O:14][CH2:15][C:16]1[O:17][CH:18]=[C:19]([O:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20](=[O:22])[CH:21]=1)/[C:7]([O-:9])=[O:8].[Na+:47]
Reactant: C=CCOC(=O)/C(=N\OCc1cc(=O)c(OC(c2ccccc2)c2ccccc2)co1)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C([O-])/C(=N\OCc1cc(=O)c(OC(c2ccccc2)c2ccccc2)co1)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
A solution of allyl (E)-2-(2-thienyl)-2-[(5-benzhydryloxy-4-pyranon-2-yl methoxy)imino]acetate (from Step 1, Example 2, 2.09 gm, 4.17 mmol), in a mixture of methylene chloride and ethyl acetate (25 ml: 55 ml) was treated with sodium 2-ethylhexanoate (693 mg, 4.17 mmol), triphenylphosphine (109 mg, 0.417 mmol) and Pd (PPh3)4 (193 mg, 0.167 mmol) and the mixture was stirred at room temperature for 5 hrs. The resulting precipitate was filtered, washed with a mixture of ether-ethyl acetate (1:1) and dried in vacuo to afford a white solid (2.0 gm, 99% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:15])[C:10]([O:12]CC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[Si:1]([O:8][C@@H:9]([CH3:15])[C:10]([OH:12])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of (S)-(−)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate (10.0 g, 43.04 mmol) in THF (430 mL) at 0° C. was added an aqueous LiOH solution (0.2 M, 430 mL). After stirring at room temperature for 5 hr, the reaction mixture was concentrated to 50% of the original volume and extracted with petroleum ether (2×80 mL). The ether extracts were combined and extracted with a saturated aqueous NaHCO3 solution (80 mL). The aqueous layers were combined and acidified to pH 3 to 4 with an aqueous KHSO4 solution (1 M, 175 mL). The aqueous solution was extracted with petroleum ether (3×300 mL) and the combined organic layers were dried over Na2SO4 and concentrated to afford 6.96 g of (S)-(−)-2-(tert-butyldimethylsilyloxy)propanoic acid as colorless oil (79% yield). 1H NMR (CDCl3): δ 4.26 (q, 1H, J=6.8 Hz, —CH), 1.35 (d, 3H, J=6.8 Hz, —CH3), 0.82 (s, 9H, Si—(CH3)3), 0.03 (s, 3H, Si—CH3), 0.02 (s, 3H, Si—CH3).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[OH:22][CH2:23][CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[O:22][CH2:23][CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=1
Reactant: OCCSc1ccccc1
Reactant: COc1ccccc1CNc1ccc2c(I)cccc2n1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1ccc2c(OCCSc3ccccc3)cccc2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
(5-Iodo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (0.4 g, 1 mMol) and 2-hydroxyethyl-phenylsulfide (0.32 g, 2 mMol) were heated in toluene together with CuI (10 Mol-%), phenantroline (20 Mol-%) and CsCO3 (0.67 g, 2 mMol) to 100° C. for 24 h. After cooling to ambient temperature the reaction mixture was extracted twice with toluene, the combined organic phases were extracted with water and subsequently dried with sodium sulfate. After evaporation the residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 100:0->60:40 gradient) to yield (2-methoxy-benzyl)-[5-(2-phenylsulfanyl-ethoxy)-quinolin-2-yl]-amine (0.4 g, 93%) as a yellow oil,