Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:30])[CH:16]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:18]([NH:17][CH:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:31])=[O:8])=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 95.3 %

Procedure:
N-benzoyl-D,L-leucyl-L-proline benzyl ester (2 g) was dissolved in methanol (40 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (1.5 g, 98%), which was directly used for the next reaction.
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[CH3:20][N:21]([CH3:43])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1>>[C:10]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:18]=[CH:19][C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH3:20])[CH3:43])=[O:42])=[CH:28][CH:29]=3)=[CH:3][C:4]1=2)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CN(C)CCCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)CCCNC(=O)c1ccc(-c2cnc3c(c2)N(C(=O)c2ccccc2)CCN3)cc1
Yield: 44 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50 mg) was reacted with N-(3-dimethylamino-propyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide as in General Procedure 4A to give the title compound as a light yellow solid (44% yield). M.p. 94° C., LCMS: m/z=444.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.72-1.80 (m, 2H), 2.27 (s, 6H), 2.48-2.53 (t, J=5.8 Hz, 2H), 3.48-3.54 (m, 2H), 3.67-3.73 (m, 2 h), 3.98-4.04 (m, 2H), 5.44 (bs, 1H), 7.10-7.18 (m, 2H), 7.36-7.48 (m, 6H), 7.69 (d, J=8.1 Hz, 2H), 8.07 (s, 1H), 8.42 (bs, 1H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:14](OCC)(=[O:16])C.CCCCCC>CO>[OH:16][CH2:14][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH3:6])=[O:8]
Reactant: CCOC(C)=O
Reactant: O=C1CCCCCO1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)CCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
ε-Caprolactone (12.50 g, 109.51 mM) was dissolved in methanol (125 ml), and a sulfuric acid solution (1 ml, 0.01 mM) was slowly added thereto. The resulting mixture was stirred at room temperature for 2 days. After the completion of reaction, methanol was removed under reduced pressure, and then ice water was poured into the residue. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 10.18 g of the title compound (yield 64%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]=[O:14].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:8]=[C:7]2[CH:13]=[O:14]
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(C=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of NaH (6.6 g, 166 mmol, 1.10 eq) in DMF (500 mL) was added a solution of 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151 mmol, 1.00 eq) in DMF (50 mL) dropwise at 0° C. over a period of 30 min. The mixture was stirred at room temperature for 2 h, then SEM-Cl (26.4 g, 159 mmol, 1.08 eq) was added dropwise and the mixture was stirred at room temperature for another 3 h. Then the mixture was poured into an ice-water mixture (1000 mL) and extracted with EtOAc (300 mL×3), the organic phases were combined, dried over Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by flash chromatography on silica gel (PE: EtOAc=20:1→10:1) to afford 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (XIX) as a mixture of regioisomers (53.0 g, 151 mmol, 100% yield) as a yellow oil. ESIMS found for C14H19BrN2O2Si m/z 355 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:18][OH:19])[CH:7]=[C:8]([O:15][CH2:16][CH3:17])[C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:16]([O:15][C:8]1[CH:7]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH:18]=[O:19])[CH3:17]
Reactant: CCOc1cc(CO)cc(OCC)c1-n1cccc1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Yield: 89.1 %

Procedure:
To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminum hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h, the excess of hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL), and activated MnO2 (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](I)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:36]([C:25]1([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH3:37]
Reactant: CCI
Reactant: O=C1c2ccccc2C(=O)C1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)c2ccccc2C1=O
Yield: 67 %

Procedure:
The alkylation of (II) by ethyl iodide is performed in boiling acetone with potassium carbonate as basic agent. 2-Ethyl-2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (III) is formed in over 67% yield and easily isolated from the acetone solution by concentrating it and diluting with water. A high purity (III) is obtained after crystallization from methanol or ethanol.
Reaction SMILES: ClC1C=C([CH2:8][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.C(OC(=O)CSC1SC(N)=NC=1)C.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47](CCC(O)=O)=[CH:46]1>>[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]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)=[CH:46]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)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 3-(1H-indol-3-yl)-propionic acid (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13]2)#[N:2].[ClH:28]>O1CCOCC1.C(#N)C>[ClH:28].[CH2:13]1[C:14]2[C:9](=[C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:27]=[CH:26][CH:25]=3)[C:1]#[N:2])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11][NH:12]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2OCc2cccc(C#N)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: N#Cc1cccc(COc2cccc3c2CCNC3)c1
Reaction time: 2 h

Procedure:
tert-Butyl 5-(3-cyanobenzyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.040 g) was taken up in 4 M HCl in dioxane (2 mL) at r.t. After stirring for 2 h. the reaction was complete and this was concentrated under reduced pressure to give a residue. This was taken up in acetonitrile and reconcentrated under reduced pressure two times to give crude 3-[(1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl]benzonitrile HCl salt (0.040 g) as a solid residue. Analytical LCMS (M+H)+: m/z=265.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[N:10]#[C:11]Br.C(N(CC)CC)C>CC(C)=O>[CH3:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][C:11]#[N:10]
Reactant: Cc1cc(Cl)ccc1O
Reactant: N#CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1OC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-chloro-2-methyl phenol (10g, 0.07 mol) and cyanogen bromide (7.4g, 0.07 mol) were stirred in acetone at 0° C. and triethylamine (9.7 ml, 0.07 mol) was added dropwise. The mixture was stirred at 0° C. for a further 2 hours, then filtered. The filtrate was concentrated using a rotary evaporator to leave the desired product as a fawn solid. This was used without further purification. The melting point of the product, after recrystallisation from ethyl acetate/hexane, was found to be 60° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:24])=O>CN(C)C=O>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
To 9.4 g. (30 mmoles) of 2,5-di-(2,2,2-trifluoroethoxy)benzoic acid are added 2 drops of dimethylformamide and 7.2 ml. (11.9 g., 100 mmoles) of purified thionyl chloride. The product is refluxed for 3 hours and excess thionyl chloride is removed in vacuo (steam bath/water aspirator pressure). Last traces of thionyl chloride are removed by similar vacuum distillation with added benzene. The product is 2,5-di-(2,2,2-trifluoroethoxy)benzoyl chloride according to infrared spectral measurement.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH2:23][CH3:24]>CN1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH3:24]
Reactant: CCI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCn1c2c(c(=O)n1-c1ccccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 45.9 %

Procedure:
A solution of (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 39; 151 mg, 0.5 mmol) and iodoethane (0.21 mL, 2.58 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown gum which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2-chloro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (76 mg, 46%) as an off-white foam. ES(+)-MS (M+H) 331.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C@@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][C@@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1
Reactant: O=C1CC[C@@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CC[C@@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((S)-5-oxopyrrolidin-2-ylmethyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.017 g, 0.041 mmol) in EtOH/H2O (1:1, 10 mL) is added 10% Pd/C (0.010 g). The mixture is stirred under an atmosphere of H2 for 2 h at RT. The catalyst is filtered through Celite and is washed with EtOH. The solvent is evaporated off to the title compound. 1H NMR (DMSO-d6) δ 7.16 (d, J=8 Hz, 1H), 6.53 is, 1H), 6.36 (d, J=5.81 Hz, 1H), 4.08 (s, 2H), 2.42 (m, 2H), 2.07 (t, J=6.57 Hz, 2H), 1.51 (m, 3H); HPLC retention time=0.55 min (method A). (M−H)−=326.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:47][O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30]([NH:47][O:48][CH:49]5[CH2:54][CH2:53][CH2:52][CH2:51][O:50]5)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c2ccccc21
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c2ccccc21

Procedure:
A suspension of (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (150 mg, 0.348 mmol) in DCM (4 ml) was treated with TEA (0.070 ml, 0.52 mmol) and then with EDC (99 mg, 0.52 mmol), HOBt (70 mg, 0.52 mmol) and NH2OTHP (49 mg, 0.42 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)acrylamide as a white solid [LC-MS: (ES+) MH+: 531]. The solid was suspended in DCM (5 ml) and treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C to give, after purification by preparative HPLC, (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl]-N-hyroxy-acrylamide (40 mg, trifluoroacetic salt) as a brown solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].[I:19][CH2:20]I.O>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH2:20][I:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)C1CCOCC1
Reactant: ICI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CI)CCOCC1
Temperature: 25 °C
Yield: 53 %

Procedure:
Lithium diisopropylamide (10.9 ml of 2.0M solution in heptane/tetrahydrofuran/ethylbenzene) was added to a stirred solution of tetrahydropyran-4-carboxylic acid methyl ester (3.00 g) in tetrahydrofuran (50 ml) at 0° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes before dropwise addition of diiodomethane (2.51 ml). Stirring was continued for a further hour during which it warmed to room temperature. The reaction was poured into water (50 ml) and then extracted with diethyl ether (3×40 ml). The combined organics were washed with water (2×20 ml), 2 M hydrochloric acid (20 ml), water (20 ml) and brine (20 ml). After drying (MgSO4), filtering and evaporating under reduced pressure a yellow oil was obtained which was purified by column chromatography eluting with 3:1 hexaneldiethyl ether to give the title compound as a colourless oil (3.11 g, 53%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:5]([NH:17][C:1]([NH:17][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[S:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCN
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCNC(=S)NCCCCCCCCCCCC
Yield: 75.5 %

Procedure:
Thiophosgene (10.0 mls, 0.13 moles) is added dropwise to a stirred solution of dodecylamine (100 g, 0.54 moles) in toluene (210 mls). The mixture is heated to reflux for four hours then cooled in an icebath. The precipitate is filtered off, rinsed with toluene then ether, and dried, then treated with hot dilute HCl, rinsed with water and redried. Recrystallization from ethyl acetate gave the product (40.5 g), mp 75°-78° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:33][C@H:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N)nc3sc(CCc4ccc(F)cc4)nc23)C1
Yield: 42.1 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (150 mg, 0.42 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (3.0 mmol, 492 μL) and tert-butyl 3-(S)-aminopyrrolidine-1-carboxylate (2.1 mmol). The reaction mixture was refluxed for 40 hours whereupon the mixture was extracted with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (81 mg) which was characterized by its mass spectrum: MS m/z (%): 459 ([M+H]+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: OB(O)c1cccs1
Reactant: O=Cc1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc2c(-c3cccs3)n[nH]c2c1
Yield: 70.6 %

Procedure:
A mixture of 1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), thiophen-2-ylboronic acid (47 mg, 0.37 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and 2M Na2CO3 (0.28 mL, 0.55 mmol) in DME/H2O (2 mL/1 mL) was heated under reflux for 16 hours. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc (10 to 20%) in DCM as the eluent to provide the title compound as a pale yellow solid (29 mg, 70%). 1H NMR (400 MHz, CD3OD) δ ppm 10.09 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.48 (d, J=5.0 Hz, 1H), 7.19 (dd, J=4.8, 3.8 Hz, 1H); MS ESI 229.0 (100) [M+H]+, calcd for [C12H8N2OS+H]+ 229.04.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C(#N)C.[F-].[K+].O>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:24]2[CH:2]=[CH:3][C:4]3[C:8]4[CH:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]=3[N:23]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2ccc(-c3ccc(CO)cc3)nc21
Temperature: 140 °C
Yield: 172.5 %

Procedure:
A mixture of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (700 mg, 0.87 mmol), 4-hydroxymethylbenzeneboronic acid (400 mg, 1.32 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.5 mg, 0.064 mmol) in acetonitrile (21 mL) and 2N aqueous potassium fluoride solution (21 mL) was divided equally across two 25 mL microwave vials. Each vial was degassed with nitrogen for 10 minutes before the mixtures were heated under microwave irradiation at 140° C. for 30 minutes. The reaction mixtures were allowed to cool to ambient temperature, combined and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (50 mL) and left to air dry. The resultant grey solid was purified by flash column chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane). The isolated solid was then triturated with hot t-BME to afford the title compound as a light grey solid (646 mg, 26%). LCMS (Method B): RT=4.11 min, M+H+=431.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH2:24]([NH2:27])[CH2:25][CH3:26]>>[ClH:2].[ClH:1].[ClH:2].[CH2:24]([NH:27][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:17][CH2:16][CH2:15][CH3:14])[CH:15]=1)[CH:10]=2)[CH2:25][CH3:26]
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Reactant: CCCN
Agent: Cl
Product: CCCNCCOc1ccc2cc3ccc(OCCNCCC)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and n-propylamine as described in Example 15, giving 1.20 g. of the desired product as yellow crystals, m.p. 250°-252° C.